U.S. patent application number 15/164394 was filed with the patent office on 2016-12-08 for solid forms comprising(-)-o-desmethylvenlafaxine and uses thereof.
The applicant listed for this patent is Sunovion Pharmaceuticals Inc.. Invention is credited to Roger P. Bakale, Norman Kim, Sharon M. Laughlin, Patrick Mousaw, Kevin Plunkett, Michael Sizensky, John R. Snoonian, Harold S. Wilkinson.
Application Number | 20160355457 15/164394 |
Document ID | / |
Family ID | 39432564 |
Filed Date | 2016-12-08 |
United States Patent
Application |
20160355457 |
Kind Code |
A1 |
Sizensky; Michael ; et
al. |
December 8, 2016 |
Solid Forms Comprising(-)-O-Desmethylvenlafaxine And Uses
Thereof
Abstract
Solid forms comprising a compound useful in the treatment,
prevention and management of various conditions and diseases are
provided herein. In particular, the invention provides solid forms
comprising (-)-O-desmethylvenlafaxine, including salts thereof,
having utility for the treatment, prevention and management of
conditions and disorders including, but not limited to, affective
disorders such as depression, bipolar and manic disorders,
attention deficit disorder, attention deficit disorder with
hyperactivity, Parkinson's disease, epilepsy, cerebral function
disorders, obesity and weight gain, incontinence, dementia and
related disorders.
Inventors: |
Sizensky; Michael; (South
Grafton, MA) ; Wilkinson; Harold S.; (Westborough,
MA) ; Snoonian; John R.; (Bolton, MA) ; Kim;
Norman; (Westford, MA) ; Laughlin; Sharon M.;
(Hudson, MA) ; Bakale; Roger P.; (Downington,
MA) ; Plunkett; Kevin; (Walpole, MA) ; Mousaw;
Patrick; (Rutland, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sunovion Pharmaceuticals Inc. |
Marlborough |
MA |
US |
|
|
Family ID: |
39432564 |
Appl. No.: |
15/164394 |
Filed: |
May 25, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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12070888 |
Feb 21, 2008 |
|
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15164394 |
|
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60902950 |
Feb 21, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 13/10 20180101;
C07B 2200/07 20130101; A61P 15/12 20180101; C07C 215/64 20130101;
A61P 25/00 20180101; A61P 25/14 20180101; A61P 15/00 20180101; A61P
25/22 20180101; C07C 213/10 20130101; C07B 2200/13 20130101; A61P
25/04 20180101; A61P 29/00 20180101; C07C 2601/14 20170501; A61P
25/24 20180101 |
International
Class: |
C07C 215/64 20060101
C07C215/64 |
Claims
1. A crystal form of a hydrochloride salt of the stereomerically
pure compound of formula (I): ##STR00004##
2. The crystal form of claim 1 which contains water.
3. The crystal form of claim 2 which is Form A.
4. The crystal form of claim 3 wherein the molar ratio of water to
(-)-O-desmethylvenlafaxine hydrochloride salt is approximately one
to one.
5. The crystal form of claim 3 wherein the water is present in an
amount of between about 4% and about 8% of the total mass of the
sample.
6. The crystal form of claim 2 which has a thermal gravimetric
analysis weight loss of between about 4% and about 8% of the total
mass of the sample when heated from about 25.degree. C. to about
110.degree. C.
7. The crystal form of claim 2 which has a differential scanning
calorimetry endotherm with an onset temperature of between about 50
and about 125.degree. C.
8. The crystal form of claim 2 which has a temperature of
dehydration between about 50 and about 125.degree. C.
9. The crystal form of claim 2 which exhibits an X-ray powder
diffraction peak at the approximate position of 21.35.degree.
2.theta..
10. The crystal form of claim 9 which exhibits X-ray powder
diffraction peaks at the approximate positions of 14.48, 19.05 and
22.96.degree. 2.theta..
11. The crystal form of claim 3, which is obtained by crystallizing
a hydrochloride salt of the compound of formula (1) from water or a
solvent mixture comprising water.
12. The crystal form of claim 2, which is prepared from Form B of a
hydrochloride salt of (-)-O-desmethylvenlafaxine.
13. A pharmaceutical composition comprising the crystal form of
claim 1 and a pharmaceutically acceptable diluent, excipient or
carrier.
14. A pharmaceutical composition comprising the crystal form of
claim 2 and a pharmaceutically acceptable diluent, excipient or
carrier.
15. The pharmaceutical composition of claim 14, wherein the crystal
form is in a pure form.
16. A method of treating, preventing or managing depression, which
comprises administering to a human in need of such treatment,
prevention or management a therapeutically or prophylactically
effective amount of the pharmaceutical composition of claim 15.
17. The method of claim 16, wherein the amount of stereomerically
pure (-)-O-desmethylvenlafaxine hydrochloride salt is insufficient
to cause adverse effects associated with the administration of
racemic venlafaxine.
18. A method of treating, preventing or managing pain, which
comprises administering to a human in need of such treatment,
prevention or management a therapeutically or prophylactically
effective amount of the pharmaceutical composition of claim 15.
19. The method of claim 18, wherein the pain is chronic pain.
20. The method of claim 18, wherein the amount of stereomerically
pure (-)-O-desmethylvenlafaxine hydrochloride salt is insufficient
to cause adverse effects associated with the administration of
racemic venlafaxine.
21. A method of treating, preventing or managing anxiety, which
comprises administering to a human in need of such treatment,
prevention or management a therapeutically or prophylactically
effective amount of the pharmaceutical composition of claim 15.
22. The method of claim 21, wherein the amount of stereomerically
pure (-)-O-desmethylvenlafaxine hydrochloride salt is insufficient
to cause adverse effects associated with the administration of
racemic venlafaxine.
23. The method of claim 21, wherein the anxiety is obsessive
compulsive disorder.
24. A method of treating, preventing or managing incontinence,
which comprises administering to a human in need of such treatment,
prevention or management a therapeutically or prophylactically
effective amount of the pharmaceutical composition of claim 15.
25. The method of claim 24, wherein the amount of stereomerically
pure (-)-O-desmethylvenlafaxine hydrochloride salt is insufficient
to cause adverse effects associated with the administration of
racemic venlafaxine.
26. The method of claim 24, wherein the incontinence is fecal
incontinence, overflow incontinence, passive incontinence, reflex
incontinence, stress urinary incontinence, urge incontinence, or
urinary exertional incontinence of the urine.
27. The method of claim 16, 18, 21 or 21, wherein the
stereomerically pure (-)-O-desmethylvenlafaxine hydrochloride salt
is administered by intravenous infusion, transdermal delivery or
orally as a tablet or capsule.
28. The method of claim 27, wherein the amount administered is from
about 10 mg to about 1000 mg per day.
29. The method of claim 27, wherein the amount administered is from
about 50 mg to about 500 mg per day.
30. The method of claim 27, wherein the amount administered is from
about 75 mg to about 300 mg per day.
31. The method of claim 18, wherein the stereomerically pure
(-)-O-desmethylvenlafaxine hydrochloride salt is administered by
intravenous infusion, transdermal delivery or orally as a tablet or
capsule.
32. The method of claim 31, wherein the amount administered is from
about 10 mg to about 1000 mg per day.
33. The method of claim 31, wherein the amount administered is from
about 50 mg to about 500 mg per day.
34. The method of claim 31, wherein the amount administered is from
about 75 mg to about 300 mg per day.
35. The method of claim 21, wherein the stereomerically pure
(-)-O-desmethylvenlafaxine hydrochloride salt is administered by
intravenous infusion, transdermal delivery or orally as a tablet or
capsule.
36. The method of claim 35, wherein the amount administered is from
about 10 mg to about 1000 mg per day.
37. The method of claim 35, wherein the amount administered is from
about 50 mg to about 500 mg per day.
38. The method of claim 35, wherein the amount administered is from
about 75 mg to about 300 mg per day.
39. The method of claim 24, wherein the stereomerically pure
(-)-O-desmethylvenlafaxine hydrochloride salt is administered by
intravenous infusion, transdermal delivery or orally as a tablet or
capsule.
40. The method of claim 39, wherein the amount administered is from
about 10 mg to about 1000 mg per day.
41. The method of claim 39, wherein the amount administered is from
about 50 mg to about 500 mg per day.
42. The method of claim 39, wherein the amount administered is from
about 75 mg to about 300 mg per day.
Description
[0001] This application claims the benefit of U.S. provisional
application 60/902,950, filed Feb. 21, 2007, the contents of which
are incorporated by reference herein in their entirety.
1. FIELD of THE INVENTION
[0002] The present invention relates to solid forms comprising
stereomerically pure (-)-O-desmethylvenlafaxine, including salts
thereof, compositions comprising the solid forms, methods of making
the solid forms and methods of their use for the treatment of
various diseases and/or disorders.
2. BACKGROUND of THE INVENTION
[0003] Each pharmaceutical compound has an optimal therapeutic
blood concentration and a lethal concentration. The bioavailability
of the compound determines the dosage strength in the drug
formulation necessary to obtain the ideal blood level. If the drug
can crystallize as two or more crystal forms differing in
bioavailability, the optimal dose will depend on the crystal form
present in the formulation. Some drugs show a narrow margin between
therapeutic and lethal concentrations. Chloramphenicol-3-palmitate
(CAPP), for example, is a broad-spectrum antibiotic known to
crystallize in at least three polymorphic crystal forms and one
amorphous form. The most stable form, A, is marketed. The
difference in bioactivity between this polymorph and another form,
B, is a factor of eight, thus creating the possibility of fatal
overdosages of the compound if unwittingly administered as Form B
due to alterations during processing and/or storage. Therefore,
regulatory agencies, such as the United States Food and Drug
Administration, have begun to place tight controls on the
polymorphic content of the active component in solid dosage forms.
In general, for drugs that exist in polymorphic forms, if anything
other than the pure, thermodynamically preferred polymorph is to be
marketed, the regulatory agency may require batch-by-batch
monitoring. Thus, it becomes important for both medical and
commercial reasons to produce and market the pure drug in its most
thermodynamically stable polymorph, substantially free of other
kinetically favored polymorphs.
[0004] New solid forms of a pharmaceutical agent can further the
development of formulations for the treatment of illnesses. For
instance, solid forms of salts of a compound are known in the
pharmaceutical art to affect, for example, the solubility,
dissolution rate, bioavailability, chemical and physical stability,
flowability, fractability, and compressibility of the compound as
well as the safety and efficacy of drug products based on the
compound (see, e.g., Byrn, S. R., Pfeiffer, R. R., and Stowell, J.
G. (1999) Solid-State Chemistry of Drugs, 2nd ed., SSCI, Inc: West
Lafayette, Ind.).
[0005] Accordingly, identification of a solid form comprising a
salt or free base of a compound with optimal physical and chemical
properties will advance the development of the compound as a
pharmaceutical. Useful physical and chemical properties include:
reproducible preparation, non-hygroscopicity, aqueous solubility,
stability to visible and ultraviolet light, low rate of degradation
under accelerated stability conditions of temperature and humidity,
low rate of isomerization of between isomeric forms, and safety for
long-term administration to humans. Crystallinity is often
desirable, although in some instances enhanced dissociation
profiles may be attained via preparation of an amorphous form.
[0006] O-desmethylvenlafaxine, chemically named
1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol, is a
metabolite of the compound venlafaxine, a hydrochloride salt of
which is currently commercially available under the trade name
Effexor.RTM.. Effexor.RTM., which is a racemic mixture of the (+)
and (-) enantiomers of venlafaxine, is indicated for the treatment
of depression. Racemic O-desmethylvenlafaxine has been exemplified
as a fumarate salt in U.S. Pat. No. 4,535,186, and a succinate and
formate salts were disclosed in U.S. Pat. Nos. 6,673,838 and
7,001,920, respectively. Stereomerically pure
(-)-O-desmethylvenlafaxine and its pharmaceutically acceptable
salts have been disclosed in U.S. Pat. Nos. 6,342,533 B1, 6,441,048
B1 and 6,911,479 B2.
[0007] We have discovered that not all of the solid forms
comprising (-)-O-desmethylvenlafaxine, including salts thereof, are
equally useful, as assessed by the list of properties described
above. Thus, the present invention addresses the need for improved
solid forms comprising (-)-O-desmethylvenlafaxine for, e.g.,
manufacturing and formulation.
3. SUMMARY of THE INVENTION
[0008] The present invention provides novel solid forms, including
amorphous forms and crystal forms, comprising
(-)-O-desmethylvenlafaxine and salts thereof, having particular
utility for the treatment, prevention or management of conditions
and disorders including, but not limited to, affective disorders
such as depression, bipolar and manic disorders, attention deficit
disorder, attention deficit disorder with hyperactivity, anxiety
disorders, panic disorder, social anxiety disorder, post traumatic
stress disorder, premenstrual dysphoric disorder, borderline
personality disorder, fibromyalgia, agoraphobia, obsessive
compulsive disorder, anorexia and bulimia nervosa, obesity, weight
gain, Gilles de la Tourette Syndrome, Shy-Drager syndrome,
Alzheimer's disease, Parkinson's disease, epilepsy, narcolepsy,
smoking cessation, drug craving, neurally mediated sexual
dysfunction, pain, including chronic and neuropathic pain, cerebral
function disorders, senile dementia, memory loss, amnesia/amnestic
syndrome; disturbances of consciousness, coma, speech disorders,
Lennox syndrome, autism, hyperkinetic syndrome, schizophrenia,
migraine, obesity and weight gain, incontinence, chronic fatigue
syndrome, sleep apnea, menopausal vasomotor symptoms such as hot
flashes, disorders ameliorated by inhibition of neuronal monoamine
uptake, related disorders, and the mental disorders described in
the American Psychiatric Association's Diagnostic and Statistical
Manual of Mental Disorders, 4.sup.th edition (DSM-IV).
[0009] In certain embodiments, the solid forms are crystal forms,
including polymorphs, of salts of the invention. The invention also
encompasses both hydrous and anhydrous crystal forms comprising
(-)-O-desmethylvenlafaxine and salts thereof. Without intending to
be limited by any particular theory, the storage stability,
compressibility, bulk density or dissolution properties of the
solid forms are believed to be beneficial for manufacturing,
formulation and bioavailability of (-)-O-desmethylvenlafaxine and
salts thereof. In certain embodiments, the invention provides
pharmaceutical compositions comprising the solid forms and methods
of their use for the treatment, prevention and/or management of
conditions and disorders including, but not limited to, affective
disorders such as depression, bipolar and manic disorders,
attention deficit disorder, attention deficit disorder with
hyperactivity, anxiety disorders, panic disorder, social anxiety
disorder, post traumatic stress disorder, premenstrual dysphoric
disorder, borderline personality disorder, fibromyalgia,
agoraphobia, obsessive compulsive disorder, anorexia and bulimia
nervosa, obesity, weight gain, Gilles de la Tourette Syndrome,
Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease,
epilepsy, narcolepsy, smoking cessation, drug craving, neurally
mediated sexual dysfunction, pain, including chronic and
neuropathic pain, cerebral function disorders, senile dementia,
memory loss, amnesia/amnestic syndrome; disturbances of
consciousness, coma, speech disorders, Lennox syndrome, autism,
hyperkinetic syndrome, schizophrenia, migraine, obesity and weight
gain, incontinence, chronic fatigue syndrome, sleep apnea,
menopausal vasomotor symptoms such as hot flashes, disorders
ameliorated by inhibition of neuronal monoamine uptake, related
disorders, and the mental disorders described in the American
Psychiatric Association's Diagnostic and Statistical Manual of
Mental Disorders, 4.sup.th edition (DSM-IV).
[0010] In certain embodiments, the compounds and compositions of
the invention are used to treat, prevent and/or manage the
above-described conditions and disorders while reducing or avoiding
adverse effects including, but not limited to, sustained
hypertension, headache, asthenia, sweating, nausea, constipation,
somnolence, dry mouth, dizziness, insomnia, nervousness, anxiety,
blurred or blurry vision, and abnormal ejaculation/orgasm or
impotence in males.
[0011] The solid forms are prepared from
(-)-O-desmethylvenlafaxine, which is described in U.S. Pat. Nos.
6,342,533 B1, 6,441,048 B1 and 6,911,479 B2, which are hereby
incorporated by reference in their entireties.
(-)-O-desmethylvenlafaxine has the following structure (I):
##STR00001##
[0012] In certain embodiments, the present invention provides
crystalline salts of (-)-O-desmethylvenlafaxine. In other
embodiments, the present invention provides crystalline
hydrochloride salts of (-)-O-desmethylvenlafaxine. In certain
embodiments, crystalline hydrochloride salts of
(-)-O-desmethylvenlafaxine possess unexpected excellent properties,
described in detail below. In certain embodiments, the present
invention provides polymorphs of the hydrochloric acid salts of
(-)-O-desmethylvenlafaxine. In certain embodiments, the present
invention provides solvates of the hydrochloride salts of
(-)-O-desmethylvenlafaxine. In certain embodiments, the present
invention provides polymorphs of solvates of the hydrochloride
salts of (-)-O-desmethylvenlafaxine. In certain embodiments, the
present invention provides hydrates of the hydrochloride salts of
(-)-O-desmethylvenlafaxine. In certain embodiments, the present
invention provides polymorphs of hydrates of the hydrochloride
salts of (-)-O-desmethylvenlafaxine. In certain embodiments, the
present invention provides amorphous salts of
(-)-O-desmethylvenlafaxine. In certain embodiments, the present
invention provides amorphous hydrochloride salts of
(-)-O-desmethylvenlafaxine.
[0013] In certain embodiments, the present invention provides
pharmaceutical compositions comprising a crystal form, a
crystalline salt form, a polymorph of a salt form, a solvate of a
salt form, a hydrate of a salt form or an amorphous salt form of
the invention and/or a pharmaceutically acceptable diluent,
excipient or carrier. In certain embodiments, the present invention
further provides methods for the treatment, prevention and/or
management of one or more of the following conditions or disorders:
affective disorders such as depression, bipolar and manic
disorders, attention deficit disorder, attention deficit disorder
with hyperactivity, anxiety disorders, panic disorder, social
anxiety disorder, post traumatic stress disorder, premenstrual
dysphoric disorder, borderline personality disorder, fibromyalgia,
agoraphobia, obsessive compulsive disorder, anorexia and bulimia
nervosa, obesity, weight gain, Gilles de la Tourette Syndrome,
Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease,
epilepsy, narcolepsy, smoking cessation, drug craving, neurally
mediated sexual dysfunction, pain, including chronic and
neuropathic pain, cerebral function disorders, senile dementia,
memory loss, amnesia/amnestic syndrome; disturbances of
consciousness, coma, speech disorders, Lennox syndrome, autism,
hyperkinetic syndrome, schizophrenia, migraine, obesity and weight
gain, incontinence, chronic fatigue syndrome, sleep apnea,
menopausal vasomotor symptoms such as hot flashes, disorders
ameliorated by inhibition of neuronal monoamine uptake, related
disorders, and the mental disorders described in the American
Psychiatric Association's Diagnostic and Statistical Manual of
Mental Disorders, 4th edition (DSM-IV), wherein such methods
comprise administering to a subject, e.g., a human, in need of such
treatment, prevention and/or management a therapeutically and/or
prophylactically effective amount of solid form of the invention.
The present invention also provides methods for the treatment,
prevention and/or management of conditions and disorders including,
but not limited to, affective disorders such as depression, bipolar
and manic disorders, attention deficit disorder, attention deficit
disorder with hyperactivity, anxiety disorders, panic disorder,
social anxiety disorder, post traumatic stress disorder,
premenstrual dysphoric disorder, borderline personality disorder,
fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia
and bulimia nervosa, obesity, weight gain, Gilles de la Tourette
Syndrome, Shy-Drager syndrome, Alzheimer's disease, Parkinson's
disease, epilepsy, narcolepsy, smoking cessation, drug craving,
neurally mediated sexual dysfunction, pain, including chronic and
neuropathic pain, cerebral function disorders, senile dementia,
memory loss, amnesia/amnestic syndrome; disturbances of
consciousness, coma, speech disorders, Lennox syndrome, autism,
hyperkinetic syndrome, schizophrenia, migraine, obesity and weight
gain, incontinence, chronic fatigue syndrome, sleep apnea,
menopausal vasomotor symptoms such as hot flashes, disorders
ameliorated by inhibition of neuronal monoamine uptake, related
disorders, and the mental disorders described in the American
Psychiatric Association's Diagnostic and Statistical Manual of
Mental Disorders, 4.sup.th edition (DSM-IV), comprising
administering to a subject, e.g., a human, in need of such
treatment, prevention or management a/or and prophylactically
effective amount of a solid form of the invention.
[0014] In Certain embodiments, the present invention provides
methods of making, isolating and/or characterizing the solid forms
of the invention.
[0015] In certain embodiments, the novel solid forms of the
invention are useful as active pharmaceutical ingredients for the
preparation of formulations for use in animals or humans. In
certain embodiments, the present invention encompasses the use of
these solid forms as a final drug product. In certain embodiments,
the solid forms, including crystal forms, amorphous forms and final
drug products of the invention are useful, for example, for the
treatment, prevention or management of conditions and disorders
listed above.
4. BRIEF DESCRIPTION of THE DRAWINGS
[0016] FIG. 1 provides a thermal gravimetric analysis thermogram of
a sample comprising Form A of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0017] FIG. 2 provides a differential scanning calorimetry
thermogram of a sample comprising Form A of the hydrochloride salt
of (-)-O-desmethylvenlafaxine;
[0018] FIG. 3 provides an X-ray powder diffraction pattern of a
sample comprising Form A of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0019] FIG. 4 provides an infrared spectrum of a sample comprising
Form A of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
[0020] FIG. 5 provides a Raman spectrum of a sample comprising Form
A of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
[0021] FIG. 6 provides a moisture sorption isotherm of a sample
comprising Form A of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0022] FIG. 7 provides the asymmetric unit of the crystal structure
of Form A obtained by single-crystal X-ray diffraction on a sample
comprising Form A of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0023] FIG. 8 provides an X-ray powder diffraction pattern
simulated from single crystal X-ray diffraction data obtained on a
sample comprising Form A of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0024] FIG. 9 provides a thermal gravimetric analysis thermogram of
a sample comprising Form B of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0025] FIG. 10 provides a differential scanning calorimetry
thermogram of a sample comprising Form B of the hydrochloride salt
of (-)-O-desmethylvenlafaxine;
[0026] FIG. 11 provides an X-ray powder diffraction pattern of a
sample comprising Form B of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0027] FIG. 12 provides an infrared spectrum of a sample comprising
Form B of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
[0028] FIG. 13 provides a Raman spectrum of a sample comprising
Form B of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
[0029] FIG. 14 provides a moisture sorption isotherm of a sample
comprising Form B of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0030] FIG. 15 provides a thermal gravimetric analysis thermogram
of a sample comprising Form C of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0031] FIG. 16 provides a differential scanning calorimetry
thermogram of a sample comprising Form C of the hydrochloride salt
of (-)-O-desmethylvenlafaxine;
[0032] FIG. 17 provides an X-ray powder diffraction pattern of a
sample comprising Form C of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0033] FIG. 18 provides an infrared spectrum of a sample comprising
Form C of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
[0034] FIG. 19 provides a Raman spectrum of a sample comprising
Form C of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
[0035] FIG. 20 provides a moisture sorption isotherm of a sample
comprising Form C of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0036] FIG. 21 provides a thermal gravimetric analysis thermogram
of a sample comprising Form D of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0037] FIG. 22 provides a differential scanning carlorimetry
thermogram of a sample comprising Form D of the hydrochloride salt
of (-)-O-desmethylvenlafaxine;
[0038] FIG. 23 provides an X-ray powder diffraction pattern of a
sample comprising Form D of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0039] FIG. 24 provides a thermal gravimetric analysis thermogram
of a sample comprising Form E of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0040] FIG. 25 provides a differential scanning calorimetry
thermogram of a sample comprising Form E of the hydrochloride salt
of (-)-O-desmethylvenlafaxine;
[0041] FIG. 26 provides an X-ray powder diffraction pattern of a
sample comprising Form E of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0042] FIG. 27 provides an infrared spectrum of a sample comprising
Form E of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
[0043] FIG. 28 provides a Raman spectrum of a sample comprising
Form E of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
[0044] FIG. 29 provides a moisture sorption isotherm of a sample
comprising Form E of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0045] FIG. 30 provides a thermal gravimetric analysis thermogram
of a sample comprising Form F of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0046] FIG. 31 provides a differential scanning calorimetry
thermogram of a sample comprising Form F of the hydrochloride salt
of (-)-O-desmethylvenlafaxine;
[0047] FIG. 32 provides an X-ray powder diffraction pattern of a
sample comprising Form F of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0048] FIG. 33 provides an X-ray powder diffraction pattern
simulated from single crystal X-ray diffraction data obtained on a
sample comprising Form F of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0049] FIG. 34 provides an infrared spectrum of a sample comprising
Form F of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
[0050] FIG. 35 provides a Raman spectrum of a sample comprising
Form F of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
[0051] FIG. 36 provides moisture sorption isotherm of a sample
comprising Form F of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0052] FIG. 37 provides the asymmetric unit of the crystal
structure of Form F obtained by single-crystal X-ray diffraction on
a sample comprising Form F of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0053] FIG. 38 provides a thermal gravimetric analysis thermogram
of a sample comprising Form G of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0054] FIG. 39 provides a differential scanning calorimetry
thermogram of a sample comprising Form G of the hydrochloride salt
of (-)-O-desmethylvenlafaxine;
[0055] FIG. 40 provides an X-ray powder diffraction pattern of a
sample comprising Form G of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0056] FIG. 41 provides a moisture sorption isotherm of a sample
comprising Form G of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0057] FIG. 42 provides a thermal gravimetric analysis thermogram
of a sample comprising Form H of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0058] FIG. 43 provides a differential scanning calorimetry
thermogram of a sample comprising Form H of the hydrochloride salt
of (-)-O-desmethylvenlafaxine;
[0059] FIG. 44 provides an X-ray powder diffraction pattern of a
sample comprising Form H of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0060] FIG. 45 provides a thermal gravimetric analysis thermogram
of a sample comprising Form I of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0061] FIG. 46 provides a differential scanning calorimetry
thermogram of a sample comprising Form I of the hydrochloride salt
of (-)-O-desmethylvenlafaxine;
[0062] FIG. 47 provides an X-ray powder diffraction pattern of a
sample comprising Form I of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0063] FIG. 48 provides an X-ray powder diffraction pattern of a
sample comprising Form J of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0064] FIG. 49 provides an X-ray powder diffraction pattern of a
sample comprising Form K of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0065] FIG. 50 provides an X-ray powder diffraction pattern
simulated from single crystal X-ray diffraction data obtained on a
sample comprising Form K of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0066] FIG. 51 provides a thermal gravimetric analysis thermogram
of a sample comprising Form L of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0067] FIG. 52 provides a differential scanning calorimetry
thermogram of a sample comprising Form L of the hydrochloride salt
of (-)-O-desmethylvenlafaxine;
[0068] FIG. 53 provides an X-ray powder diffraction pattern of a
sample comprising Form L of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0069] FIG. 54 provides an X-ray powder diffraction pattern of a
sample comprising a desolvated solvate belonging to isostructural
family 1 of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0070] FIG. 55 provides a thermal gravimetric analysis thermogram
of a sample comprising an amorphous form of the hydrochloride salt
of (-)-O-desmethylvenlafaxine;
[0071] FIG. 56 provides a modulated differential scanning
calorimetry thermogram of a sample comprising an amorphous form of
the hydrochloride salt of (-)-O-desmethylvenlafaxine;
[0072] FIG. 57 provides an X-ray powder diffraction pattern of a
sample comprising an amorphous form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine;
[0073] FIG. 58 provides a moisture sorption isotherm of a sample
comprising an amorphous form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine.
5. DETAILED DESCRIPTION of THE INVENTION
5.1 Definitions
[0074] As used herein, the term (-)-O-desmethylvenlafaxine means
the compound that is chemically named
(-)-1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]
cyclohexanol.
[0075] As used herein, the term "pharmaceutically acceptable salts"
refers to salts prepared from pharmaceutically acceptable,
relatively non-toxic acids, including inorganic acids and organic
acids. Suitable acids include acetic, benzenesulfonic, benzoic,
camphorsulfonic, carbonic, citric, dihydrogenphosphoric,
ethenesulfonic, fumaric, galactunoric, gluconic, glucuronic,
glutamic, hydrobromic, hydrochloric, hydriodic, isobutyric,
isethionic, lactic, maleic, malic, malonic, mandelic,
methanesulfonic, monohydrogencarbonic, monohydrogenphosphoric,
monohydrogensulfuric, mucic, nitric, pamoic, pantothenic,
phosphoric, phthalic, propionic, suberic, succinic, sulfuric,
tartaric, toluenesulfonic, including p-toluenesulfonic
m-toluenesulfonic and o-toluenesulfonic acids, and the like (see,
e.g., Berge et al., J. Pharm. Sci., 66:1-19 (1977); Stahl and
Wermuth, Handbook of Pharmaceutical Salts, Wiley VCH, (2002)). Also
included are salts of other relatively non-toxic compounds that
possess acidic character, including amino acids, such as arginine
and the like, and other compounds, such as aspirin, ibuprofen,
saccharin, and the like. Particularly preferred are hydrochloric,
hydrobromic, methanesulfonic, and sulfuric acids, and most
particularly preferred is the hydrochloride salt. Acid addition
salts can be obtained by contacting the neutral form of such
compounds with a sufficient amount of the desired acid, either neat
or in a suitable inert solvent. As solids, salts can exist in
crystalline and/or amorphous modifications.
[0076] Particular salts described below include "hydrochloride
salts," "hydrochloric acid salts," and "HCl salts" of
(-)-O-desmethylvenlafaxine of the invention. A hydrochloride salt,
hydrochloric acid salt or HCl salt is an acid addition salt formed
using hydrochloric acid.
[0077] The term "solid forms" and related terms used herein, unless
otherwise specified, refers to crystal forms and amorphous forms
comprising (-)-O-desmethylvenlafaxine, and specifically includes
crystal forms and amorphous forms comprising salts of
(-)-O-desmethylvenlafaxine.
[0078] The term "crystalline" and related terms used herein, when
used to describe a substance, component or product, means that the
substance, component or product is crystalline as determined by
X-ray diffraction. See, e.g., Remington's Pharmaceutical Sciences,
18.sup.th ed., Mack Publishing, Easton, Pa., 173 (1990); The United
States Pharmacopeia, 23.sup.rd ed., 1843-1844 (1995).
[0079] The term "crystal forms" and related terms herein refers to
the various crystalline modifications of a given substance,
including, but not limited to, polymorphs, solvates, hydrates,
co-crystals and other molecular complexes, as well as salts,
solvates of salts, hydrates of salts, other molecular complexes of
salts, and polymorphs thereof. Crystal forms of a substance can be
obtained by a number of methods, as known in the art. Such methods
include, but are not limited to, melt recrystallization, melt
cooling, solvent recrystallization, recrystallization in confined
spaces such as, e.g., in nanopores or capillaries,
recrystallization on surfaces or templates such as, e.g., on
polymers, recrystallization in the presence of additives, such as,
e.g., co-crystal counter-molecules, desolvation, dehydration, rapid
evaporation, rapid cooling, slow cooling, vapor diffusion,
sublimation, grinding and solvent-drop grinding.
[0080] The terms "polymorphs," "polymorphic forms" and related
terms herein refer to two or more crystal forms that are composed
of the same molecule, molecules or ions. Different polymorphs may
have different physical properties such as, for example, melting
temperatures, heats of fusion, solubilities, dissolution rates
and/or vibrational spectra as a result of the arrangement or
conformation of the molecules or ions in the crystal lattice (see,
e.g., Byrn, S. R., Pfeiffer, R. R., and Stowell, J. G. (1999)
Solid-State Chemistry of Drugs, 2nd ed., SSCI, Inc.: West
Lafayette, Ind.). The differences in physical properties exhibited
by polymorphs affect pharmaceutical parameters such as storage
stability, compressibility and density (important in formulation
and product manufacturing), and dissolution rate (an important
factor in bioavailability). Differences in stability can result
from changes in chemical reactivity (e.g., differential oxidation,
such that a dosage form discolors more rapidly when comprised of
one polymorph than when comprised of another polymorph) or
mechanical changes (e.g., tablets crumble on storage as a
kinetically favored polymorph converts to thermodynamically more
stable polymorph) or both (e.g., tablets of one polymorph are more
susceptible to breakdown at high humidity). As a result of
solubility/dissolution differences, in the extreme case, some
polymorphic transitions may result in lack of potency or, at the
other extreme, toxicity. In addition, the physical properties of
the crystal may be important in processing, for example, one
polymorph might be more likely to form solvates or might be
difficult to filter and wash free of impurities (i.e., particle
shape and size distribution might be different between
polymorphs).
[0081] The term "solvate" and "solvated," as used herein, refer to
a crystal form of a substance which contains solvent. The term
"hydrate" and "hydrated" refer to a solvate wherein the solvent is
water. "Polymorphs of solvates" refers to the existence of more
than one crystal form for a particular solvate composition.
Similarly, "polymorphs of hydrates" refers to the existence of more
than one crystal form for a particular hydrate composition.
[0082] The term "desolvated solvate," as used herein, refers to a
crystal form of a substance which can be prepared by removing the
solvent from a solvate.
[0083] The term "isostructural family," as used herein, refers to a
series of two or more crystal forms of a substance which have a
common structural similarity, including approximately similar
interplanar spacing in the crystal lattice. (A more detailed
account of crystal lattices can be found in Chapters 2 and 3 of
Stout and Jensen, X-Ray Structure Determination: A Practical Guide,
MacMillan Co., New York (1968)). Due to their common structural
similarity, members of an isostructural family of crystal forms
typically have similar, but not necessarily identical, X-ray powder
diffraction patterns. An isostructural family may be based upon a
substance that is a neutral molecule, a salt or a molecular
complex. The series may be composed of solvates, including
hydrates, and desolvated solvate crystal forms of the substance.
Solvated members of an isostructural family of crystal forms
typically contain one or more solvents, including water, in the
crystal lattice. The solvent or solvents in the crystal lattice may
be the solvent or solvents of crystallization used in preparing the
crystal form. Typical solvents of crystallization include water and
all classes of organic and other types of laboratory solvents,
including, but not limited to: alcohols, such as methanol, ethanol,
n-propanol, isopropanol, n-butanol, sec-butanol, t-butanol,
hydroxyphenyl, glycerol, and the like; carbonyl-containing
solvents, such as acetone, methyl ethyl ketone, formic acid, acetic
acid, ethyl acetate, butyl acetate, N,N-dimethylformamide, and the
like; hydrocarbons, such as pentane, hexane, cyclohexane, benzene,
toluene, xylenes, and the like; halogenated solvents, such as
dichlormethane, chloroform, carbon tetrachloride, and the like; and
laboratory solvents containing other heteroatoms and/or functional
groups, such as acetonitrile, tetrahydrofuran, diethyl ether,
diisopropyl ether, carbon disulfide, dimethyl sulfoxide,
1,4-dioxane, nitrobenzene, nitromethane, pyridine, and the
like.
[0084] The term "amorphous," "amorphous form," and related terms
used herein mean that the material, substance, component or product
under consideration is not crystalline as determined by X-ray
diffraction. Amorphous forms of a substance can be obtained by a
number of methods, as known in the art. Such methods include, but
are not limited to, heating, melt cooling, rapid melt cooling,
solvent evaporation, rapid solvent evaporation, desolvation,
sublimation, grinding, cryo-grinding and freeze drying.
[0085] Techniques for characterizing crystal forms and amorphous
forms include, but are not limited to, thermal gravimetric analysis
(TGA), differential scanning calorimetry (DSC), X-ray powder
diffractometry (XRPD), single crystal X-ray diffractometry,
vibrational spectroscopy, e.g., infrared (IR) and Raman
spectroscopy, solid-state NMR, optical microscopy, hot stage
optical microscopy, scanning electron microscopy (SEM), electron
crystallography and quantitative analysis, particle size analysis
(PSA), surface area analysis, solubility studies and dissolution
studies.
[0086] As used herein, and unless otherwise specified, the terms
"about" and "approximately," when used in connection with doses,
amounts, or weight percent of ingredients of a composition or a
dosage form, mean a dose, amount, or weight percent that is
recognized by those of ordinary skill in the art to provide a
pharmacological effect equivalent to that obtained from the
specified dose, amount, or weight percent. Specifically, the terms
"about" and "approximately," when used in this context, contemplate
a dose, amount, or weight percent within 15%, within 10%, within
5%, within 4%, within 3%, within 2%, within 1%, or within 0.5% of
the specified dose, amount, or weight percent.
[0087] As used herein, and unless otherwise specified, the terms
"about" and "approximately," when used in connection with a numeric
value or range of values which is provided to describe a particular
solid form, e.g., a specific temperature or temperature range, such
as, for example, that describing a melting, dehydration,
desolvation or glass transition; a mass change, such as, for
example, a mass change as a function of temperature or humidity; a
solvent or water content, in terms of, for example, mass or a
percentage; or a peak position, such as, for example, in analysis
by IR or Raman spectroscopy or XRPD; indicate that the value or
range of values may deviate to an extent deemed reasonable to one
of ordinary skill in the art while still describing the particular
solid form. Specifically, the terms "about" and "approximately,"
when used in this context, indicate that the numeric value or range
of values may vary by 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,
0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% of the
recited value or range of values while still describing the
particular solid form.
[0088] As used herein and unless otherwise indicated, the term
"stereomerically pure" means a composition that comprises one
stereoisomer of a compound and is substantially free of other
stereoisomers of that compound. For example, a stereomerically pure
composition of a compound having one chiral center will be
substantially free of the opposite enantiomer of the compound. A
stereomerically pure composition of a.compound having two chiral
centers will be substantially free of other diastereomers of the
compound. In certain embodiments, a stereomerically pure compound
comprises greater than about 80 percent by weight of one
stereoisomer of the compound and less than about 20 percent by
weight of other stereoisomers of the compound, greater than about
90 percent by weight of one stereoisomer of the compound and less
than about 10 percent by weight of the other stereoisomers of the
compound, greater than about 95 percent by weight of one
stereoisomer of the compound and less than about 5 percent by
weight of the other stereoisomers of the compound, greater than
about 97 percent by weight of one stereoisomer of the compound and
less than about 3 percent by weight of the other stereoisomers or
greater than about 99 percent by weight of one stereoisomer of the
compound and less than about 1 percent by weight of the other
stereoisomers of the compound.
[0089] As used herein and unless otherwise indicated, the term
"enantiomerically pure" means a stereomerically pure composition of
a compound having one chiral center.
[0090] As used herein to describe a compound, the term
"substantially free of its (+) stereoisomer" means that the
compound is made up of a significantly greater proportion of its
(-) stereoisomer than of its optical antipode (i.e., its (+)
stereoisomer). In certain embodiments of the invention, the term
"substantially free of its (+) stereoisomer" means that the
compound is made up of at least about 90% by weight of its (-)
stereoisomer and about 10% by weight or less of its (+)
stereoisomer. In certain embodiments of the invention, the term
"substantially free of its (+) stereoisomer" means that the
compound is made up of at least about 95% by weight of its (-)
stereoisomer and about 5% by weight or less of its (+)
stereoisomer. In certain embodiments, the term "substantially free
of its (+) stereoisomer" means that the compound is made up of at
least about 99% by weight of its (-) stereoisomer and about 1% or
less of its (+) stereoisomer. In certain embodiments, the term
"substantially free of its (+) stereoisomer" means that the
compound is made up of approximately 100% by weight of its (-)
stereoisomer. The above percentages are based on the total amount
of the combined stereoisomers of the compound. The terms
"substantially optically pure (-)-O-desmethylvenlafaxine,"
"optically pure (-)-O-desmethylvenlafaxine" and "(-) isomer of
O-desmethylvenlafaxine" all refer to (40-desmethylvenlafaxine that
is substantially free of its (+) stereoisomer. The terms
"substantially optically pure (-)-O-desmethylvenlafaxine,"
"optically pure (-)-O-desmethylvenlafaxine" and "(-) isomer of
O-desmethylvenlafaxine" all refer to (-)-O-desmethylvenlafaxine
that is substantially free of its (+) stereoisomer.
[0091] As used herein, a crystalline or amorphous form that is
"pure," i.e., substantially free of other crystalline or amorphous
forms, contains less than about 10 percent by weight of one or more
other crystalline or amorphous form, less than about 5 percent by
weight of one or more other crystalline or amorphous form, less
than about 3 percent by weight of one or more other crystalline or
amorphous form, or less than about 1 percent by weight of one or
more other crystalline or amorphous form.
[0092] As used herein and unless otherwise indicated, a composition
that is "substantially free" of a compound means that the
composition contains less than about 20 percent by weight, less
than about 10 percent by weight, less than about 5 percent by
weight, less than about 3 percent by weight, or less than about 1
percent by weight of the compound.
[0093] As used herein, and unless otherwise specified, the terms
"treat," "treating" and "treatment" refer to the eradication or
amelioration of a disease or disorder, or of one or more symptoms
associated with the disease or disorder. In certain embodiments,
the terms refer to minimizing the spread or worsening of the
disease or disorder resulting from the administration of one or
more prophylactic or therapeutic agents to a subject with such a
disease or disorder. In some embodiments, the terms refer to the
administration of a compound provided herein, with or without other
additional active agent, after the onset of symptoms of the
particular disease.
[0094] As used herein, and unless otherwise specified, the terms
"prevent," "preventing" and "prevention" refer to the prevention of
the onset, recurrence or spread of a disease or disorder, or of one
or more symptoms thereof. In certain embodiments, the terms refer
to the treatment with or administration of a compound provided
herein, with or without other additional active compound, prior to
the onset of symptoms, particularly to patients at risk of disease
or disorders provided herein. The terms encompass the inhibition or
reduction of a symptom of the particular disease. Patients with
familial history of a disease in particular are candidates for
preventive regimens in certain embodiments. In addition, patients
who have a history of recurring symptoms are also potential
candidates for the prevention. In this regard, the term
"prevention" may be interchangeably used with the term
"prophylactic treatment."
[0095] As used herein, and unless otherwise specified, the terms
"manage," "managing" and "management" refer to preventing or
slowing the progression, spread or worsening of a disease or
disorder, or of one or more symptoms thereof. Often, the beneficial
effects that a subject derives from a prophylactic and/or
therapeutic agent do not result in a cure of the disease or
disorder. In this regard, the term "managing" encompasses treating
a patient who had suffered from the particular disease in an
attempt to prevent or minimize the recurrence of the disease.
[0096] As used herein, the term "affective disorder" includes
depression, attention deficit disorder, attention deficit disorder
with hyperactivity, bipolar and manic conditions, and the like. The
terms "attention deficit disorder" (ADD) and "attention deficit
disorder with hyperactivity" (ADDH), or attention
deficit/hyperactivity disorder (AD/HD), are used herein in
accordance with the accepted meanings as found in the Diagnostic
and Statistical Manual of Mental Disorders, 4.sup.th ed., American
Psychiatric Association (1997) (DSM-IV.TM.).
[0097] As used herein, the term "a method of treating depression"
means relief from the symptoms of depression which include, but are
not limited to, changes in mood, feelings of intense sadness,
despair, mental slowing, loss of concentration, pessimistic worry,
agitation, and self-deprecation. Physical changes may also be
relieved, including insomnia, anorexia, weight loss, decreased
energy and libido, and abnormal hormonal circadian rhythms.
[0098] As used herein, the term "a method of treating, preventing
or managing obesity or weight gain" means reduction of weight, or
prevention of or relief from being overweight, gaining weight, or
obesity; all of which are usually due to extensive consumption of
food.
[0099] As used herein, the term "a method of treating, preventing
or managing disorders ameliorated by inhibition of neuronal
monoamine reuptake" means prevention of or relief from symptoms of
disease states associated with abnormal neuronal monoamine levels;
such symptoms are reduced by way of neuronal monoamine reuptake
inhibition. Monoamines, the reuptake of which are inhibited by the
compounds or compositions of the present invention, include, but
are not limited to, noradrenaline (or norepinephrine), serotonin
and dopamine. Disorders treated by neuronal monoamine reuptake
inhibition include, but are not limited to, Parkinson's disease and
epilepsy.
[0100] As used herein, the term "method of treating, preventing or
managing Parkinson's disease" means prevention of or relief from
the symptoms of Parkinson's disease which include, but are not
limited to, slowly increasing disability in purposeful movement,
tremors, bradykinesia, rigidity, and a disturbance of posture in
humans.
[0101] As used herein, the term "a method for treating, preventing
or managing cerebral function disorders" means prevention of or
relief from the disease states associated with cerebral function
disorders involving intellectual deficits which include but are not
limited to, senile dementia, Alzheimer's type dementia, memory
loss, amnesia/amnestic syndrome, disturbances of consciousness,
coma, lowering of attention, speech disorders, Parkinson's disease,
Lennox syndrome, autism, hyperkinetic syndrome and schizophrenia.
Also within the meaning of cerebral function disorders are
disorders caused by cerebrovascular diseases including, but not
limited to, cerebral infarction, cerebral bleeding, cerebral
arteriosclerosis, cerebral venous thrombosis, head injuries, and
the like and where symptoms include disturbances of consciousness,
senile dementia, coma, lowering of attention, speech disorders, and
the like.
[0102] The terms "obsessive-compulsive disorder," "substance
abuse," "pre-menstrual syndrome," "anxiety," "eating disorders" and
"migraine" are used herein in a manner consistent with their
accepted meanings in the art. See, e.g., DSM-IV.TM.. The terms
"method of treating, preventing or managing," "method of treating,"
"method of preventing" and "method of managing" when used in
connection with these disorders mean the amelioration, prevention
or relief from the symptoms and/or effects associated with these
disorders. Without being limited by any theory, the treatment,
prevention or management of certain of these disorders may be
related to the activity of the active ingredient(s) as inhibitors
of serotonin uptake.
[0103] As used herein, the term "a method of treating, preventing
or managing incontinence" means prevention of or relief from the
symptoms of incontinence including involuntary voiding of feces or
urine, and dribbling or leakage or feces or urine which may be due
to one or more causes including but not limited to pathology
altering sphincter control, loss of cognitive function,
overdistention of the bladder, hyper-reflexia and/or involuntary
urethral relaxation, weakness of the muscles associated with the
bladder or neurologic abnormalities.
[0104] As used herein, and unless otherwise specified, a
"therapeutically effective amount" of a compound is an amount
sufficient to provide a therapeutic benefit in the treatment or
management of a disease or disorder, or to delay or minimize one or
more symptoms associated with the disease or disorder. A
therapeutically effective amount of a compound means an amount of
therapeutic agent, alone or in combination with other therapies,
which provides a therapeutic benefit in the treatment or management
of the disease or disorder. The term "therapeutically effective
amount" can encompass an amount that improves overall therapy,
reduces or avoids symptoms or causes of disease or disorder, or
enhances the therapeutic efficacy of another therapeutic agent.
[0105] As used herein, and unless otherwise specified, a
"prophylactically effective amount" of a compound is an amount
sufficient to prevent a disease or disorder, or prevent its
recurrence. A prophylactically effective amount of a compound means
an amount of therapeutic agent, alone or in combination with other
agents, which provides a prophylactic benefit in the prevention of
the disease. The term "prophylactically effective amount" can
encompass an amount that improves overall prophylaxis or enhances
the prophylactic efficacy of another prophylactic agent.
[0106] The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients (and in
the specified amounts, if indicated), as well as any product which
results, directly or indirectly, from combination of the specified
ingredients in the specified amounts. By "pharmaceutically
acceptable" it is meant the diluent, excipient or carrier must be
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof.
[0107] The term "therapeutically and/or prophylactically effective
amount" refers to the amount of the subject solid form that will
elicit the biological or medical response of a tissue, system,
animal or human that is being sought by the researcher,
veterinarian, medical doctor or other clinician or that is
sufficient to prevent development of or alleviate to some extent
one or more of the symptoms of the disease being treated.
[0108] The term "subject" is defined herein to include animals such
as mammals, including, but not limited to, primates (e.g., humans),
cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the
like. In specific embodiments, the subject is a human.
[0109] In certain embodiments, the invention provides compounds
which comprise (-)-O-desmethylvenlafaxine in a prodrug form.
Prodrugs of the compounds described herein are structurally
modified forms of the compound that readily undergo chemical
changes under physiological conditions to provide the compound.
Additionally, prodrugs can be converted to the compound by chemical
or biochemical methods in an ex vivo environment. For example,
prodrugs can be slowly converted to a compound when placed in a
transdermal patch reservoir with a suitable enzyme or chemical
reagent. Prodrugs are often useful because, in some situations,
they may be easier to administer than the compound, or parent drug.
They may, for instance, be bioavailable by oral administration
whereas the parent drug is not. The prodrug may also have improved
solubility in pharmaceutical compositions over the parent drug. A
wide variety of prodrug derivatives are known in the art, such as
those that rely on hydrolytic cleavage or oxidative activation of
the prodrug. An example, without limitation, of a prodrug would be
a compound which is administered as a carbamate (the "prodrug"),
but then is metabolically hydrolyzed to the phenol, the active
entity. Additional examples include petidyl derivatives of a
compound.
[0110] In certain embodiments, the compounds of the present
invention may also contain unnatural proportions of atomic isotopes
at one or more of the atoms. For example, the compound may be
labeled with radioactive and/or nonradioactive isotopes, such as
for example deuterium (.sup.2H), tritium (.sup.3H), iodine-125
(.sup.125I), sulfur-35 (.sup.35S), carbon-13 (.sup.13C) or
carbon-14 (.sup.14C). Radiolabeled compounds are useful as
therapeutic agents, e.g., cancer therapeutic agents, research
reagents, e.g., binding assay reagents, and diagnostic agents,
e.g., in vivo imaging agents. All isotopic variations of the
compound of the present invention, whether radioactive or not, are
intended to be encompassed within the scope of the present
invention.
5.2 Embodiments of the Invention
[0111] In certain embodiments, the present invention is directed to
solid forms comprising stereomerically pure
(-)-O-desmethylvenlafaxine and salts thereof, including solvated
and hydrated forms thereof, and amorphous forms, and compositions
comprising the solid forms alone or in combination with other
active ingredients, methods of their use in the treatment,
prevention and/or management of conditions and disorders including,
but not limited to, affective disorders such as depression, bipolar
and manic disorders, attention deficit disorder, attention deficit
disorder with hyperactivity, anxiety disorders, panic disorder,
social anxiety disorder, post traumatic stress disorder,
premenstrual dysphoric disorder, borderline personality disorder,
fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia
and bulimia nervosa, obesity, weight gain, Gilles de la Tourette
Syndrome, Shy-Drager syndrome, Alzheimer's disease, Parkinson's
disease, epilepsy, narcolepsy, smoking cessation, drug craving,
neurally mediated sexual dysfunction, pain, including chronic and
neuropathic pain, cerebral function disorders, senile dementia,
memory loss, amnesia/amnestic syndrome; disturbances of
consciousness, coma, speech disorders, Lennox syndrome, autism,
hyperkinetic syndrome, schizophrenia, migraine, obesity and weight
gain, incontinence, chronic fatigue syndrome, sleep apnea,
menopausal vasomotor symptoms such as hot flashes, disorders
ameliorated by inhibition of neuronal monoamine uptake, related
disorders, and the mental disorders described in the American
Psychiatric Association's Diagnostic and Statistical Manual of
Mental Disorders, 4.sup.th edition (DSM-IV). While not intending to
be bound by any particular theory, the storage stability,
compressibility, density or dissolution properties of the solid
forms are beneficial for manufacturing, formulation and
bio-availability of the present invention.
[0112] In one embodiment, the condition or disorder is an affective
disorder. In another embodiment, the condition or disorder is
depression. In another embodiment, the condition or disorder is an
anxiety disorder. In another embodiment, the condition or disorder
is a cerebral function disorder. In another embodiment, the
condition or disorder is fibromyalgia. In another embodiment, the
condition or disorder is pain. In another embodiment, the condition
or disorder is neuropathic pain.
[0113] In certain embodiments, solid forms of the invention are
those that are characterized by physical properties, e.g.,
stability, solubility and dissolution rate, appropriate for
clinical and therapeutic dosage forms. Certain solid forms of the
invention are characterized by physical properties, e.g., crystal
morphology, compressibility and hardness, suitable for manufacture
of a solid dosage form. Such properties can be determined using
techniques such as X-ray diffraction, microscopy, IR spectroscopy
and thermal analysis, as described herein and known in the art.
5.2.1 Salts of Stereomerically Pure (-)-O-desmethylvenlafaxine
[0114] In one embodiment, the present invention provides particular
pharmaceutically acceptable salts of (-)-O-desmethylvenlafaxine,
having utility for the treatment, prevention or management of
conditions and disorders including, but not limited to, affective
disorders such as depression, bipolar and manic disorders,
attention deficit disorder, attention deficit disorder with
hyperactivity, anxiety disorders, panic disorder, social anxiety
disorder, post traumatic stress disorder, premenstrual dysphoric
disorder, borderline personality disorder, fibromyalgia,
agoraphobia, obsessive compulsive disorder, anorexia and bulimia
nervosa, obesity, weight gain, Gilles de la Tourette Syndrome,
Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease,
epilepsy, narcolepsy, smoking cessation, drug craving, neurally
mediated sexual dysfunction, pain, including chronic and
neuropathic pain, cerebral function disorders, senile dementia,
memory loss, amnesia/amnestic syndrome; disturbances of
consciousness, coma, speech disorders, Lennox syndrome, autism,
hyperkinetic syndrome, schizophrenia, migraine, obesity and weight
gain, incontinence, chronic fatigue syndrome, sleep apnea,
menopausal vasomotor symptoms such as hot flashes, disorders
ameliorated by inhibition of neuronal monoamine uptake, related
disorders, and the mental disorders described in the American
Psychiatric Association's Diagnostic and Statistical Manual of
Mental Disorders, 4.sup.th edition (DSM-IV).
[0115] In certain embodiments, the present invention provides
hydrochloride salts of stereomerically pure
(-)-O-desmethylvenlafaxine. As shown above,
(-)-O-desmethylvenlafaxine has the general formula (I):
##STR00002##
In the hydrochloride salts of (-)-O-desmethylvenlafaxine, the acid
is according to the formula HCl.
[0116] A preferred hydrochloric acid salt of
(-)-O-desmethylvenlafaxine is the monohydrochloric acid salt,
provided by formula (II):
##STR00003##
[0117] Each salt of the invention can be made from a preparation of
stereomerically pure (-)-O-desmethylvenlafaxine or from an addition
salt of (-)-O-desmethylvenlafaxine. (-)-O-desmethylvenlafaxine can
be synthesized or obtained according to any method apparent to
those of skill in the art. In preferred embodiments,
(-)-O-desmethylvenlafaxine is prepared according to the methods
described in detail in the examples below, in U.S. Pat. Nos.
6,342,533 B1, 6,441,048 B1 and 6,911,479 B2, all of which are
hereby incorporated by reference in their entireties.
[0118] In some embodiments, (-)-O-desmethylvenlafaxine prepared by
any method can be contacted with an appropriate acid, either neat
or in a suitable solvent, to yield the salts of the invention. For
example, (-)-O-desmethylvenlafaxine can be contacted with
hydrochloric acid to yield the hydrochloride salts of the
invention.
[0119] In some embodiments, an (-)-O-desmethylvenlafaxine addition
salt prepared by any method known in the art can be contacted with
an appropriate acid, either neat or in a suitable solvent, to yield
the salts of the invention. For example, (-)-O-desmethylvenlafaxine
cyclohexylphenylglycolic acid salt can be contacted with
hydrochloric acid to yield the hydrochloride salts of the
invention.
[0120] As shown below, certain forms comprising the hydrochloride
salt of (-)-O-desmethylvenlafaxine display superior stability,
solubility and hygroscopicity properties in comparison to other
forms comprising (-)-O-desmethylvenlafaxine.
5.2.2 Solid Forms Comprising Stereomerically Pure
(-)-O-desmethylvenlafaxine and Salts Thereof
[0121] The present invention also provides crystal forms comprising
stereomerically pure (-)-O-desmethylvenlafaxine and salts thereof,
having particular utility for the treatment, prevention or
management of conditions and disorders including, but not limited
to, affective disorders such as depression, bipolar and manic
disorders, attention deficit disorder, attention deficit disorder
with hyperactivity, anxiety disorders, panic disorder, social
anxiety disorder, post traumatic stress disorder, premenstrual
dysphoric disorder, borderline personality disorder, fibromyalgia,
agoraphobia, obsessive compulsive disorder, anorexia and bulimia
nervosa, obesity, weight gain, Gilles de la Tourette Syndrome,
Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease,
epilepsy, narcolepsy, smoking cessation, drug craving, neurally
mediated sexual dysfunction, pain, including chronic and
neuropathic pain, cerebral function disorders, senile dementia,
memory loss, amnesia/amnestic syndrome; disturbances of
consciousness, coma, speech disorders, Lennox syndrome, autism,
hyperkinetic syndrome, schizophrenia, migraine, obesity and weight
gain, incontinence, chronic fatigue syndrome, sleep apnea,
menopausal vasomotor symptoms such as hot flashes, disorders
ameliorated by inhibition of neuronal monoamine uptake, related
disorders, and the mental disorders described in the American
Psychiatric Association's Diagnostic and Statistical Manual of
Mental Disorders, 4.sup.th edition (DSM-IV). In certain
embodiments, the solid forms of the invention are crystal forms
comprising the hydrochloride salt of (-)-O-desmethylvenlafaxine
described above.
[0122] In certain embodiments, crystal forms of the invention can
be made from a preparation of (-)-O-desmethylvenlafaxine. For
instance, a salt of (-)-O-desmethylvenlafaxine can be dissolved and
then crystallized to yield crystal forms of the invention. In
particular embodiments of the invention, a hydrochloride salt of
(-)-O-desmethylvenlafaxine can be crystallized from particular
solvent mixtures, such as those described below, to yield the
crystal forms of the invention.
[0123] In one embodiment, the present invention provides Form A, a
crystal form of a hydrochloride salt of (-)-O-desmethylvenlafaxine
((-)-1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol
hydrochloride salt). In particular embodiments, Form A is a crystal
form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine.
In certain embodiments, a sample of the Form A crystal form of the
hydrochloride salt of (-)-O-desmethylvenlafaxine has a water
content ranging between about 4% and about 8% of the total mass of
the sample. In certain embodiments, Form A has a water content of
about 6% of the total mass of the sample, which is equal to about
one molar equivalent of water per mole of
(-)-O-desmethylvenlafaxine. In certain embodiments, when examined
by Karl Fisher titration according to the methods described herein,
Form A has a water content of about 5.7% by mass. In further
embodiments, Form A has a thermal gravimetric analysis thermogram
similar to that of FIG. 1. In certain embodiments, when examined by
thermal gravimetric analysis according to the methods described
herein, Form A has a weight loss corresponding to about 5.6% of the
total mass of the sample occurring between about 25 and about
110.degree. C. In certain embodiments, Form A has a differential
scanning calorimetry thermogram similar to that of FIG. 2. In
certain embodiments, when examined by differential scanning
calorimetry according to the methods described herein, Form A has
an endotherm with an onset temperature at about 93.degree. C. In
certain embodiments, the Form A crystal form of the hydrochloride
salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction
pattern similar to that of FIG. 3 using Cu K.alpha. radiation. In
certain embodiments, the Form A crystal form of the hydrochloride
salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction
pattern similar to that of FIG. 8, which was simulated for Cu
K.alpha. radiation using single-crystal X-ray diffraction
structural data obtained on Form A. In certain embodiments,
particular Form A crystal forms of the invention have major X-ray
powder diffraction pattern peaks at about 12.7, 14.5, 19.1, 21.4,
23.0, 25.5, 27.3.degree. 2.theta. using Cu K.alpha. radiation. In
certain embodiments, the Form A crystal form of the invention has
major X-ray powder diffraction pattern peaks at one, two, three,
four, five, six or seven of the X-ray powder diffraction pattern
positions of about 12.7, 14.5, 19.1, 21.4, 23.0, 25.5, 27.3.degree.
2.theta. using Cu K.alpha. radiation. In certain embodiments, the
Form A crystal form of the invention has both a water content of
about 5.7% of the total mass of the sample and major X-ray powder
diffraction pattern peaks at one, two, three, four, five, six or
seven of the X-ray powder diffraction pattern positions of about
12.7, 14.5, 19.1, 21.4, 23.0, 25.5, 27.3.degree. 2.theta. using Cu
K.alpha. radiation. In certain embodiments of the invention, Form A
has an infrared spectrum similar to that of FIG. 4. In certain
embodiments of the invention, Form A has a Raman spectrum similar
to that of FIG. 5. In certain embodiments, when analyzed at
approximately 150 K according to a method capable of determining
unit cell parameters, e.g. single crystal X-ray diffraction, Form A
has the following approximate unit cell parameters: a=6.78 .ANG.;
b=9.29 .ANG.; c=27.65 .ANG.; .alpha.=90.degree.; .beta.=90.degree.;
.gamma.=90.degree.; V=1741.39 .ANG..sup.3. In certain embodiments,
Form A crystallizes in space group P2.sub.12.sub.12.sub.1.
[0124] Without being limited by a particular theory, it has been
found that the Form A crystal form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine has excellent hygroscopicity properties.
For example, without being limited by a particular theory, when
examined by dynamic vapor sorption according to the methods
described herein, Form A gains <1% in mass upon increasing the
sample from 5% to 90% relative humidity. Further, the mass gain of
Form A as a function of relative humidity is reversible, such that,
for example, the sample loses about 1% in mass upon decreasing from
90% to 5% relative humidity. In certain embodiments, the Form A
crystal form provided herein has a moisture sorption isotherm
similar to that of FIG. 6.
[0125] In addition, without being limited by a particular theory,
it has been found that the Form A crystal form of the hydrochloride
salt of (-)-O-desmethylvenlafaxine also has excellent stability
properties.
[0126] Form A of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method of making Form
A apparent to those of skill in the art based upon the teachings
herein. In certain embodiments, Form A can be prepared by
crystallization of the hydrochloride salt of
(-)-O-desmethylvenlafaxine from a solvent system containing one or
more solvents, such as, but not limited to, water, acetone,
acetonitrile, ethanol, isopropanol, methanol, methyl ethyl ketone,
methyl t-butyl ether, heptane, hexanes toluene and mixtures
thereof. In certain embodiments, Form A may be obtained by crystal
form conversion from another crystal or amorphous form of the
hydrochloride salt of (-)-O-desmethylvenlafaxine, for instance, via
a solvent-mediated and/or water-mediated form conversion
process.
[0127] In another embodiment, the present invention provides Form
B, a crystal form of the monohydrochloride salt of
(-)-O-desmethylvenlafaxine that contains the solvent
tetrahydrofuran (THF) in the crystal lattice. In a certain
embodiment, the THF is present in the approximate ratio of 0.25
molar equivalents of THF per mole of the hydrochloride salt of
(-)-O-desmethylvenlafaxine. In terms of mass, this equates to a THF
content of approximately 6% of the total mass of a sample of Form
B. In a certain embodiment, the THF content of Form B ranges from
about 4% to about 8% of the total mass of the sample of Form B. In
certain embodiments, Form B has a thermal gravimetric analysis
thermogram similar to that of FIG. 9. In certain embodiments, when
examined by thermal gravimetric analysis according to the methods
described herein, Form B has a weight loss corresponding to about
5.7% of the total mass of the sample occurring between about 25 and
about 180.degree. C. In certain embodiments, the Form B crystal
form has a differential scanning calorimetry thermogram similar to
that of FIG. 10. In certain embodiments, when examined by
differential scanning calorimetry according to the methods
described herein, Form B has an endotherm with an onset temperature
of about 176.degree. C. and another endotherm with an onset
temperature of about 199.degree. C. In certain embodiments, Form B
has an additional endotherm with a peak temperature at about
160.degree. C. In certain embodiments, the Form B crystal form of
the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray
powder diffraction pattern similar to that of FIG. 11 using Cu
K.alpha. radiation. In certain embodiments, Form B crystal forms of
the invention have major X-ray powder diffraction pattern peaks at
about 13.1, 14.7, 18.8, 21.1, 24.2, 26.3, 29.4.degree. 2.theta.
using Cu K.alpha. radiation. In certain embodiments, the Form B
crystal form of the invention has major X-ray powder diffraction
pattern peaks at one, two, three, four, five, six or seven of the
X-ray powder diffraction pattern positions of about 13.1, 14.7,
18.8, 21.1, 24.2, 26.3, 29.4.degree. 2.theta. using Cu K.alpha.
radiation. In certain embodiments, the Form B crystal form of the
invention has both a THF content of about 6% of the total mass of
the sample and major X-ray powder diffraction pattern peaks at one,
two, three, four, five, six or seven of the X-ray powder
diffraction pattern positions of about 13.1, 14.7, 18.8, 21.1,
24.2, 26.3, 29.4.degree. 2.theta. using Cu K.alpha. radiation. In
certain embodiments, the Form B has an infrared spectrum similar to
that of FIG. 12. In certain embodiments, the Form B crystal form of
the invention has a Raman spectrum similar to that of FIG. 13. In a
certain embodiment of the invention, Form B has a dynamic vapor
sorption isotherm similar to that of FIG. 14. In certain
embodiments, when examined by dynamic vapor sorption according to
the methods described herein, Form B exhibits a gain in mass of
about 25% when increased from 5% to 95% relative humidity, followed
by a loss in mass of about 26% when decreased from 95% to 5%
relative humidity.
[0128] Form B of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method of making Form
B apparent to those of skill in the art based upon the teachings
herein. In certain embodiments, Form B can be prepared by
crystallization from solutions of the hydrochloride salt of
(-)-O-desmethylvenlafaxine in THF.
[0129] In another embodiment, the present invention provides Form
C, a crystal form of the monohydrochloride salt of
(-)-O-desmethylvenlafaxine that contains one or more of the
solvents ethyl acetate, ethyl ether and water in the crystal
lattice. In a particular embodiment, ethyl acetate is present in
the approximate ratio of 0.2 molar equivalents of ethyl acetate per
mole of the hydrochloride salt of (-)-O-desmethylvenlafaxine. In
terms of mass, this equates to an ethyl acetate content of
approximately 6% of the total mass of a sample of Form C. In a
particular embodiment, ethyl ether is present in the approximate
ratio of 0.2 molar equivalents of ethyl ether per mole of the
hydrochloride salt of (-)-O-desmethylvenlafaxine. In terms of mass,
this equates to an ethyl ether content of approximately 5% of the
total mass of a sample of Form C. In a particular embodiment, the
combined content of ethyl acetate, ethyl ether and water ranges
from about 3% to about 8% of the total mass of the sample of Form
C. In certain embodiments, Form C has a thermal gravimetric
analysis thermogram similar to that of FIG. 15. In certain
embodiments, when examined by thermal gravimetric analysis
according to the methods described herein, Form C has a weight loss
corresponding to about 5.1% of the total mass of the sample
occurring between about 25 and about 110.degree. C. In certain
embodiments, the Form C crystal form has a differential scanning
calorimetry thermogram similar to that of FIG. 16. In certain
embodiments, when examined by differential scanning calorimetry
according to the methods described herein, Form C has an endotherm
with an onset temperature of about 84.degree. C., another endotherm
with a peak temperature at about 136.degree. C., and another
endotherm with an onset temperature at about 167.degree. C. In
certain embodiments, the Form C crystal form of the hydrochloride
salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction
pattern similar to that of FIG. 17 using Cu K.alpha. radiation.
Particular Form C crystal forms of the invention have major X-ray
powder diffraction pattern peaks at about 5.8, 11.7, 14.7, 18.8,
21.0, 21.2.degree. 2.theta. using a radiation. In certain
embodiments, the Form C crystal form of the invention has major
X-ray powder diffraction pattern peaks at one, two, three, four,
five or six of the X-ray powder diffraction pattern positions of
about 5.8, 11.7, 14.7, 18.8, 21.0, 21.2.degree. 2.theta. using Cu
K.alpha. radiation. In certain embodiments, the Form C crystal form
of the invention has a combined content of ethyl acetate, ethyl
ether and water amounting to between about 3% and about 8% of the
total mass of the sample and major X-ray powder diffraction pattern
peaks at one, two, three, four, five or six of the X-ray powder
diffraction pattern positions of about 5.8, 11.7, 14.7, 18.8, 21.0,
21.2.degree. 2.theta. using Cu K.alpha. radiation. In certain
embodiments, the Form C crystal form has an infrared spectrum
similar to that of FIG. 18. In certain embodiments, the Form C
crystal form of the invention has a Raman spectrum similar to that
of FIG. 19. In certain embodiments of the invention, Form C has a
dynamic vapor sorption isotherm similar to that of FIG. 20. In
certain embodiments, when examined by dynamic vapor sorption
according to the methods described herein, Form C exhibits a gain
in mass of about 27% when increased from 5% to 95% relative
humidity, followed by a loss in mass of about 27% when decreased
from 95% to 5% relative humidity.
[0130] Form C of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method of making Form
C apparent to those of skill in the art based upon the teachings
herein. In certain embodiments, Form C can be prepared by
crystallization from solutions of the hydrochloride salt of
(-)-O-desmethylvenlafaxine in ethyl acetate, ethyl ether, water, a
mixture of two or more of these solvents, or the like.
[0131] In another embodiment, the present invention provides Form
D, a crystal form of the mono hydrochloride salt of
(-)-O-desmethylvenlafaxine that contains isopropyl alcohol (IPA)
and/or water in the crystal lattice. In one embodiment of the
invention, a sample of the Form D crystal form of the hydrochloride
salt of (-)-O-desmethylvenlafaxine has a combined IPA and water
content ranging between about 2% and about 8% of the total mass of
the sample. In certain embodiments, the Form D crystal form has a
thermal gravimetric analysis thermogram similar to that of FIG. 21.
In certain embodiments, when examined by thermal gravimetric
analysis according to the methods described herein, Form D has a
weight loss corresponding to about 5.6% of the total mass of the
sample occurring in the range of about 25 to about 150.degree. C.
In certain embodiments, the Form D crystal form has a differential
scanning calorimetry thermogram similar to that of FIG. 22. In
certain embodiments, when examined by differential scanning
calorimetry according to the methods described herein, Form D has
an endotherm with an onset temperature at about 85.degree. C. In
certain embodiments, the Form D crystal form of the hydrochloride
salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction
pattern similar to that of FIG. 23 using Cu K.alpha. radiation.
Particular Form D crystal forms of the invention have major X-ray
powder diffraction pattern peaks at about 2.4, 5.7, 6.0, 15.9,
19.1, 19.8, 20.3.degree. 2.theta. using Cu K.alpha. radiation. In
certain embodiments, the Form D crystal form of the invention has
major X-ray powder diffraction peaks at one, two, three, four,
five, six or seven of the X-ray powder diffraction pattern
positions of about 2.4, 5.7, 6.0, 15.9, 19.1, 19.8, 20.3.degree.
2.theta. using Cu K.alpha. radiation. In certain embodiments, the
Form D crystal form of the invention has both a combined IPA and
water content ranging between about 2% and about 8% of the total
mass of the sample and major X-ray powder diffraction peaks at one,
two, three, four, five, six or seven of the X-ray powder
diffraction pattern positions of about 2.4, 5.7, 6.0, 15.9, 19.1,
19.8, 20.3.degree. 2.theta. using Cu K.alpha. radiation.
[0132] Form D of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method of making Form
D apparent to those of skill in the art based upon the teachings
herein. In certain embodiments, Form D can be prepared by
crystallization from solutions of the hydrochloride salt of
(-)-O-desmethylvenlafaxine in IPA.
[0133] In one embodiment, the present invention provides Form E, a
crystal form of the monohydrochloride salt of
(-)-O-desmethylvenlafaxine that contains methyl t-butyl ether
(MTBE) and/or water in the crystal lattice. In one embodiment of
the invention, a sample of the Form E crystal form of the
hydrochloride salt of (-)-O-desmethylvenlafaxine has a combined
MTBE and water content ranging between about 4% and about 10% of
the total mass of the sample. In certain embodiments, the Form E
crystal form has a MTBE content of about 6% of the total mass of
the sample, which is equal to about 0.2 molar equivalent of MTBE
per mole of (-)-O-desmethylvenlafaxine. In certain embodiments,
Form E has a thermal gravimetric analysis thermogram similar to
that of FIG. 24. In certain embodiments, when examined by thermal
gravimetric analysis according to the methods described herein,
Form E has a weight loss corresponding to about 5.9% of the total
mass of the sample occurring in the range of about 25 to about
180.degree. C. In certain embodiments, Form E has a differential
scanning calorimetry thermogram similar to that of FIG. 25. In
certain embodiments, when examined by differential scanning
calorimetry according to the methods described herein, Form E has
an endotherm with an onset temperature at about 93.degree. C.,
followed by an endotherm with an onset temperature at about
167.degree. C. In certain embodiments, the Form E crystal form of
the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray
powder diffraction pattern similar to that of FIG. 26 using Cu
K.alpha. radiation. Particular Form E crystal forms of the
invention have major X-ray powder diffraction pattern peaks at
about 5.8, 11.9, 13.0, 14.4, 18.5, 20.9.degree. 2.theta. using Cu
K.alpha. radiation. In certain embodiments, the Form E crystal form
of the invention has major X-ray powder diffraction peaks at one,
two, three, four, five or six of the X-ray powder diffraction
pattern positions of about 5.8, 11.9, 13.0, 14.4, 18.5,
20.9.degree. 2.theta. using Cu K.alpha. radiation. In certain
embodiments, the Form E crystal form of the invention has both a
solvent content ranging between about 4% and about 10% of the total
mass of the sample and major X-ray powder diffraction peaks at one,
two, three, four, five or six of the X-ray powder diffraction
pattern positions of about 5.8, 11.9, 13.0, 14.4, 18.5,
20.9.degree. 2.theta. using Cu K.alpha. radiation. In certain
embodiments, the Form E crystal form of the invention has an
infrared spectrum similar to that of FIG. 27. In certain
embodiments, the Form E crystal form of the invention has a Raman
spectrum similar to that of FIG. 28. In certain embodiments of the
invention, Form E has a dynamic vapor sorption isotherm similar to
that of FIG. 29. In certain embodiments, when examined by dynamic
vapor sorption according to the methods described herein, Form E
exhibits a net gain in mass of about 4.7% when increased from 5% to
95% relative humidity, followed by a loss in mass of about 5.8%
when decreased from 95% to 5% relative humidity.
[0134] Form E of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method of making Form
E apparent to those of skill in the art based upon the teachings
herein. In certain embodiments, Form E can be prepared by the
dissolution of a solid form comprising the hydrochloride salt of
(-)-O-desmethylvenlafaxine in a solvent or solvent mixture
containing, for example, methanol and water, followed by subsequent
crystallization brought about by the addition of an anti-solvent,
such as methyl t-butyl ether.
[0135] In one embodiment, the present invention provides Form F, a
hydrate crystal form of the monohydrochloride salt of
(-)-O-desmethylvenlafaxine. In one embodiment of the invention, a
sample of the Form F crystal form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine has a water content ranging between
about 4% and about 8% of the total mass of the sample. In certain
embodiments, the Form F crystal form has a water content of about
6% of the total mass of the sample, which is equal to about one
molar equivalent of water per mole of (-)-O-desmethylvenlafaxine.
In certain embodiments of the invention, Form F has a thermal
gravimetric analysis thermogram similar to that of FIG. 30. In
certain embodiments, when examined by thermal gravimetric analysis
according to the methods described herein, Form F has a weight loss
corresponding to about 5.8% of the total mass of the sample
occurring in the range of about 25 to about 125.degree. C. In
certain embodiments of the invention, Form F has a differential
scanning calorimetry thermogram similar to that of FIG. 31. In
certain embodiments, when examined by differential scanning
calorimetry according to the methods described herein, Form F has
an endotherm with an onset temperature at about 89.degree. C. In
certain embodiments, the Form F crystal form of the hydrochloride
salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction
pattern similar to that of FIG. 32. In certain embodiments, the
Form F crystal form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern
similar to that of FIG. 33, which was simulated for Cu K.alpha.
radiation using single-crystal X-ray diffraction structural data
obtained on Form F. Particular Form F crystal forms of the
invention have major X-ray powder diffraction pattern peaks at
about 14.4, 16.0, 17.4, 19.0, 25.5, 26.8.degree. 2.theta. using Cu
K.alpha. radiation. In certain embodiments, the Form F crystal form
of the invention has major X-ray powder diffraction peaks at one,
two, three, four, five or six of the X-ray powder diffraction
pattern positions of about 14.4, 16.0, 17.4, 19.0, 25.5,
26.8.degree. 2.theta. using Cu K.alpha. radiation. In certain
embodiments, the Form F crystal form of the invention has both a
water content of about 6% of the total mass of the sample and major
X-ray powder diffraction peaks at one, two, three, four, five or
six of the X-ray powder diffraction pattern positions of about
14.4, 16.0, 17.4, 19.0, 25.5, 26.8.degree. 2.theta. using Cu
K.alpha. radiation. In certain embodiments, the Form F crystal form
of the invention has an infrared spectrum similar to that of FIG.
34. In certain embodiments, the Form F crystal form of the
invention has a Raman spectrum similar to that of FIG. 35. In
certain embodiments of the invention, Form F has a dynamic vapor
sorption isotherm similar to that of FIG. 36. In certain
embodiments, when examined by dynamic vapor sorption according to
the methods described herein, Form F exhibits a gain in mass of
about 32% when increased from 5% to 95% relative humidity, followed
by a loss in mass of about 33% when decreased from 95% to 5%
relative humidity. In certain embodiments, when analyzed at
approximately 173 K according to a method capable of determining
unit cell parameters, e.g. single crystal X-ray diffraction, Form F
has the following approximate unit cell parameters: a=9.29 .ANG.;
b=6.82 .ANG.; c=13.91 .ANG.; .alpha.=90.degree.;
.beta.=92.58.degree.; .gamma.=90.degree.; V=879.95 .ANG..sup.3. In
certain embodiments, Form F crystallizes in space group
P2.sub.1.
[0136] Form F of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method of making Form
F apparent to those of skill in the art based upon the teachings
herein. In certain embodiments, Form F can be prepared by the
dissolution of a solid form comprising the hydrochloride salt of
(-)-O-desmethylvenlafaxine in a solvent mixture containing, for
example, methanol and water, followed by subsequent crystallization
brought about by the addition of an anti-solvent, such as methyl
t-butyl ether.
[0137] In one embodiment, the present invention provides Form G, a
crystal form of the monohydrochloride salt of
(-)-O-desmethylvenlafaxine. In one embodiment of the invention, a
sample of the Form G crystal form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine has a water content ranging between 0%
and 6% of the total mass of the sample. In certain embodiments, the
Form G crystal form has a water content of about 3% of the total
mass of the sample, which is equal to about a half molar equivalent
of water per mole of (-)-O-desmethylvenlafaxine. In certain
embodiments, Form G has a thermal gravimetric analysis thermogram
similar to that of FIG. 38. In certain embodiments, when examined
by thermal gravimetric analysis according to the methods described
herein, Form G has a weight loss corresponding to about 3.0% of the
total mass of the sample occurring in the range of about 25 to
about 125.degree. C. In certain embodiments, Form G has a
differential scanning calorimetry thermogram similar to that of
FIG. 39. In certain embodiments, when examined by differential
scanning calorimetry according to the methods described herein,
Form G has an endotherm with an onset temperature of about
91.degree. C. In certain embodiments, the Form G crystal form of
the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray
powder diffraction pattern similar to that of FIG. 40 using Cu
K.alpha. radiation. Particular Form G crystal forms of the
invention have characteristic X-ray powder diffraction pattern
peaks at about 12.6, 15.1, 16.7, 18.8, 21.0, 25.3.degree. 2.theta.
using Cu K.alpha. radiation. In certain embodiments, the Form G
crystal form of the invention has major X-ray powder diffraction
peaks at one, two, three, four, five or six of the X-ray powder
diffraction pattern positions of about 12.6, 15.1, 16.7, 18.8,
21.0, 25.3.degree. 2.theta. using Cu K.alpha. radiation. In certain
embodiments, the Form G crystal form of the invention has both a
water content of about 0 to 6% of the total mass of the sample and
major X-ray powder diffraction peaks at one, two, three, four, five
or six of the X-ray powder diffraction pattern positions of about
12.6, 15.1, 16.7, 18.8, 21.0, 25.3.degree. 2.theta. using Cu
K.alpha. radiation. In certain embodiments of the invention, Form G
has a dynamic vapor sorption isotherm similar to that of FIG. 41.
In certain embodiments, when examined by dynamic vapor sorption
according to the methods described herein, Form G exhibits a gain
in mass of about 3% when increased from 5% to 90% relative
humidity. In certain embodiments, when examined by dynamic vapor
sorption according to the methods described herein, Form G exhibits
a gain in mass of about 23% when increased from 5% to 95% relative
humidity, and a loss in mass of about 22% when decreased from 95%
to 5% relative humidity.
[0138] Form G of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method of making Form
G apparent to those of skill in the art based upon the teachings
herein. In certain embodiments, Form G is prepared by drying the
Form A crystal form of this invention, described above and in the
examples below, over a suitable drying agent, such as, for example,
P.sub.2O.sub.5.
[0139] In another embodiment, the present invention provides Form
H, a crystal form of the monohydrochloride salt of
(-)-O-desmethylvenlafaxine that contains the solvent acetone in the
crystal lattice. In a particular embodiment, the acetone is present
in the approximate ratio of 0.2 molar equivalents of acetone per
mole of the hydrochloride salt of (-)-O-desmethylvenlafaxine. In
terms of mass, this equates to an acetone content of approximately
4% of the total mass of a sample of Form H. In a certain
embodiment, the acetone content of Form H ranges from about 2% to
about 6% of the total mass of the sample of Form H. In certain
embodiments, Form H has a thermal gravimetric analysis thermogram
similar to that of FIG. 42. In certain embodiments, when examined
by thermal gravimetric analysis according to the methods described
herein, Form H has a weight loss corresponding to about 3.7% of the
total mass of the sample occurring between about 25 and about
180.degree. C. In certain embodiments, the Form H crystal form has
a differential scanning calorimetry thermogram similar to that of
FIG. 43. In certain embodiments, when examined by differential
scanning calorimetry according to the methods described herein,
Form H has an endotherm with a peak temperature at about
180.degree. C. In certain embodiments, Form H has an additional
endotherm with a peak temperature at about 154.degree. C. In
certain embodiments, the Form H crystal form of the hydrochloride
salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction
pattern similar to that of FIG. 44 using Cu K.alpha. radiation.
Particular Form H crystal forms of the invention have major X-ray
powder diffraction pattern peaks at about 12.1, 14.6, 18.7, 21.1,
26.3.degree. 2.theta. using Cu K.alpha. radiation. In certain
embodiments, the Form H crystal form of the invention has major
X-ray powder diffraction pattern peaks at one, two, three, four or
five of the X-ray powder diffraction pattern positions of about
12.1, 14.6, 18.7, 21.1, 26.3.degree. 2.theta. using Cu K.alpha.
radiation. In certain embodiments, the Form H crystal form of the
invention has both an acetone content of about 4% of the total mass
of the sample and major X-ray powder diffraction pattern peaks at
one, two, three, four, five or six of the X-ray powder diffraction
pattern positions of about 12.1, 14.6, 18.7, 21.1, 26.3.degree.
2.theta. using Cu K.alpha. radiation.
[0140] Form H of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method of making Form
H apparent to those of skill in the art based upon the teachings
herein. In certain embodiments, Form H can be obtained by stirring
a slurry of the Form A crystal form of (-)-O-desmethylvenlafaxine
in acetone at elevated temperature, followed by filtration.
[0141] In another embodiment, the present invention provides Form
I, a crystal form of the monohydrochloride salt of
(-)-O-desmethylvenlafaxine that contains the solvent isopropanol in
the crystal lattice. In a particular embodiment, the isopropanol is
present in Form I in the approximate ratio of 0.2 molar equivalents
of isopropanol per mole of the hydrochloride salt of
(-)-O-desmethylvenlafaxine. In terms of mass, this equates to an
isopropanol content of approximately 4% of the total mass of a
sample of Form I. In a certain embodiment, the isopropanol content
of Form I ranges from about 2% to about 6% of the total mass of the
sample of Form I. In certain embodiments, Form I has a thermal
gravimetric analysis thermogram similar to that of FIG. 45. In
certain embodiments, when examined by thermal gravimetric analysis
according to the methods described herein, Form I has a weight loss
corresponding to about 4.2% of the total mass of the sample
occurring between about 25 and about 180.degree. C. In certain
embodiments, the Form I crystal form has a differential scanning
calorimetry thermogram similar to that of FIG. 46. In certain
embodiments, when examined by differential scanning calorimetry
according to the methods described herein, Form I has endotherm
with a peak temperature at about 178.degree. C. In certain
embodiments, Form I has an additional endotherm with a peak
temperature at about 158.degree. C. In certain embodiments, the
Form I crystal form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern
similar to that of FIG. 47 using Cu K.alpha. radiation. Particular
Form I crystal forms of the invention have major X-ray powder
diffraction pattern peaks at about 13.0, 14.6, 18.7, 21.0, 23.5,
26.2.degree. 2.theta. using Cu K.alpha. radiation. In certain
embodiments, the Form I crystal form of the invention has major
X-ray powder diffraction pattern peaks at one, two, three, four,
five or six of the X-ray powder diffraction pattern positions of
about 13.0, 14.6, 18.7, 21.0, 23.5, 26.2.degree. 2.theta. using Cu
K.alpha. radiation. In certain embodiments, the Form I crystal form
of the invention has both an isopropanol content of about 4% of the
total mass of the sample and major X-ray powder diffraction pattern
peaks at one, two, three, four, five or six of the X-ray powder
diffraction pattern positions of about 13.0, 14.6, 18.7, 21.0,
23.5, 26.2.degree. 2.theta. using Cu K.alpha. radiation.
[0142] Form I of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method of making Form
I apparent to those of skill in the art based upon the teachings
herein. In certain embodiments, Form I can be obtained by
precipitation from a solution of the hydrochloride salt of
(-)-O-desmethylvenlafaxine in isopropanol followed by filtration.
In certain embodiments, Form I can be obtained by fast evaporation
of an isopropanol solution of the hydrochloride salt of
(-)-O-desmethylvenlafaxine.
[0143] In another embodiment, the present invention provides Form
J, a crystal form of the monohydrochloride salt of
(-)-O-desmethylvenlafaxine that contains the solvent acetonitrile
in the crystal lattice. In a particular embodiment, the
acetonitrile is present in Form J in the approximate ratio of 0.2
molar equivalents of acetonitrile per mole of the hydrochloride
salt of (-)-O-desmethylvenlafaxine. In terms of mass, this equates
to an acetonitrile content of approximately 3% of the total mass of
a sample of Form J. In a certain embodiment, the acetonitrile
content of Form J ranges from about 1% to about 5% of the total
mass of the sample of Form J. In certain embodiments, the Form J
crystal form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern
similar to that of FIG. 48 using Cu K.alpha. radiation. Particular
Form J crystal forms of the invention have major X-ray powder
diffraction pattern peaks at about 12.2, 14.7, 16.9, 18.8, 21.0,
23.7.degree. 2.theta. using Cu K.alpha. radiation. In certain
embodiments, the Form J crystal form of the invention has major
X-ray powder diffraction pattern peaks at one, two, three, four,
five or six of the X-ray powder diffraction pattern positions of
about 12.2, 14.7, 16.9, 18.8, 21.0, 23.7.degree. 2.theta. using Cu
K.alpha. radiation. In certain embodiments, the Form J crystal form
of the invention has both an acetonitrile content of about 3% of
the total mass of the sample and major X-ray powder diffraction
pattern peaks at one, two, three, four, five or six of the X-ray
powder diffraction pattern positions of about 12.2, 14.7, 16.9,
18.8, 21.0, 23.7.degree. 2.theta. using Cu K.alpha. radiation.
[0144] Form J of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method of making Form
J apparent to those of skill in the art based upon the teachings
herein. In certain embodiments, Form J can be obtained by
precipitation from a solution of the hydrochloride salt of
(-)-O-desmethylvenlafaxine in acetonitrile followed by filtration.
In certain embodiments, Form J can be obtained by slurrying Form A
of the hydrochloride salt of (-)-O-desmethylvenlafaxine in
acetonitrile followed by filtration.
[0145] In another embodiment, the present invention provides Form
K, a crystal form of the monohydrochloride salt of
(-)-O-desmethylvenlafaxine that contains the solvent ethanol in the
crystal lattice. In a certain embodiment, the ethanol content of
Form K is less than about 13% of the total mass of the sample of
Form K, which is less than about one molar equivalent of ethanol
per mole of the hydrochloride salt of (-)-O-desmethylvenlafaxine.
In certain embodiments, the Form K crystal form of the
hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray
powder diffraction pattern similar to that of FIG. 49. In certain
embodiments, the Form K crystal form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern
similar to that of FIG. 50, which was simulated for Cu K.alpha.
radiation according to the methods described herein using
single-crystal X-ray diffraction structural data obtained for Form
K. Particular Form K crystal forms of the invention have major
X-ray powder diffraction pattern peaks at about 12.1, 13.1, 14.6,
18.7, 21.0, 21.2.degree. 2.theta. using Cu K.alpha. radiation. In
certain embodiments, the Form K crystal form of the invention has
major X-ray powder diffraction pattern peaks at one, two, three,
four, five or six of the X-ray powder diffraction pattern positions
of about 12.1, 13.1, 14.6, 18.7, 21.0, 21.2.degree. 2.theta. using
Cu K.alpha. radiation. In certain embodiments, the Form K crystal
form of the invention has both an ethanol content of less than
about 13% of the total mass of the sample and major X-ray powder
diffraction pattern peaks at one, two, three, four, five or six of
the X-ray powder diffraction pattern positions of about 12.1, 13.1,
14.6, 18.7, 21.0, 21.2.degree. 2.theta. using Cu K.alpha.
radiation. In certain embodiments, when analyzed at approximately
173 K according to a method capable of determining unit cell
parameters, e.g. single crystal X-ray diffraction, Form K has the
following approximate unit cell parameters: a=30.06 .ANG.; b=7.74
.ANG.; c=21.21 .ANG.; .alpha.=90.degree.; .beta.=134.50.degree.;
.gamma.=90.degree.; V=3517.7 .ANG..sup.3. In certain embodiments,
Form K crystallizes in space group C2.
[0146] Form K of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method of making Form
K apparent to those of skill in the art based upon the teachings
herein. In certain embodiments, Form K can be obtained by
crystallization from a solution of the hydrochloride salt of
(-)-O-desmethylvenlafaxine in an ethanol/acetone solvent
system.
[0147] In another embodiment, the present invention provides Form
L, a crystal form of the monohydrochloride salt of
(-)-O-desmethylvenlafaxine that contains the solvent
2-methyl-tetrahydrofuran in the crystal lattice. In a particular
embodiment, the 2-methyl-tetrahydrofuran is present in Form L in
the approximate ratio of between 0.1 and 0.3 molar equivalents of
2-methyl-tetrahydrofuran per mole of the hydrochloride salt of
(-)-O-desmethylvenlafaxine. In terms of mass, this equates to a
2-methyl-tetrahydrofuran content of between approximately 3% to 8%
of the total mass of a sample of Form L. In a certain embodiment,
the 2-methyl-tetrahydrofuran content of Form L ranges from about 1%
to about 10% of the total mass of the sample of Form L. In certain
embodiments, Form L has a thermal gravimetric analysis thermogram
similar to that of FIG. 51. In certain embodiments, when examined
by thermal gravimetric analysis according to the methods described
herein, Form L has a weight loss corresponding to about 2% of the
total mass of the sample occurring between about 25 and about
125.degree. C. and a weight loss corresponding to about 7% of the
total mass of the sample occurring between about 25 and about
180.degree. C. In certain embodiments, the Form L crystal form has
a differential scanning calorimetry thermogram similar to that of
FIG. 52. In certain embodiments, when examined by differential
scanning calorimetry according to the methods described herein,
Form L has an endotherm with an onset temperature at about
166.degree. C. In certain embodiments, the Form L crystal form of
the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray
powder diffraction pattern similar to that of FIG. 53 using Cu
K.alpha. radiation. Particular Form L crystal forms of the
invention have major X-ray powder diffraction pattern peaks at
about 12.0, 13.0, 14.5, 18.8, 21.0, 23.4.degree. 2.theta. using Cu
K.alpha. radiation. In certain embodiments, the Form L crystal form
of the invention has major X-ray powder diffraction pattern peaks
at one, two, three, four, five or six of the X-ray powder
diffraction pattern positions of about 12.0, 13.0, 14.5, 18.8,
21.0, 23.4.degree. 2.theta. using Cu K.alpha. radiation. In certain
embodiments, the Form L crystal form of the invention has both an
2-methyl-tetrahydrofuran content of between about 1% and about 10%
of the total mass of the sample and major X-ray powder diffraction
pattern peaks at one, two, three, four, five or six of the X-ray
powder diffraction pattern positions of about 12.0, 13.0, 14.5,
18.8, 21.0, 23.4.degree. 2.theta. using Cu K.alpha. radiation.
[0148] Form L of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method of making Form
L apparent to those of skill in the art based upon the teachings
herein. In certain embodiments, Form L can be obtained by slurrying
Form A of the hydrochloride salt of (-)-O-desmethylvenlafaxine in
2-methyl-tetrahydrofuran followed by filtration.
[0149] In another embodiment, the present invention provides
crystal forms comprising the monohydrochloride salt of
(-)-O-desmethylvenlafaxine that are members of an isostructural
family of crystal forms. Members of a particular isostructural
family of crystal forms share a certain structural similarity to
the other members of that family with regard to features such as,
for example, interplanar spacing in the crystal lattice. Structural
similarity among members of a particular isostructural family
results in some common characteristics of these crystal forms, for
example, members of an isostructural family of crystal forms
comprising the hydrochloric acid salt of (-)-O-desmethylvenlafaxine
have similar X-ray powder diffraction patterns. Each member of a
given isostructural family of crystal forms contains one or more
types of organic solvents and/or water in the crystal lattice, or
alternatively may be a desolvated solvate. Preferred solvents for
inclusion in the crystal lattice of a member of a given
isostructural family of crystal forms comprising the hydrochloric
acid salt of (-)-O-desmethylvenlafaxine include common organic
laboratory solvents and water. In other embodiments, the invention
provides desolvated solvate members of an isostructural family of
crystal forms comprising the hydrochloric acid salt of
(-)-O-desmethylvenlafaxine. A desolvated solvate is formed by the
removal from the crystal lattice of one or more types of solvents
and/or water; as a result, desolvated solvate crystal forms do not
possess substantial quantities of solvent or water in the crystal
lattice. Solvent removal may involve drying, heating and/or vacuum
methods, as well as other methods apparent to those skilled in the
art.
[0150] In one embodiment, the invention provides crystal forms
comprising the hydrochloride salt of (-)-O-desmethylvenlafaxine
belonging to isostructural family 1. In certain embodiments of the
invention, members of isostructural family 1 are selected from the
group consisting of Form B, Form C, Form H, Form I, Form J, Form K
and Form L. In a certain embodiment of the invention, a member of
isostructural family 1 of crystal forms has characteristic X-ray
powder diffraction pattern peaks at about 5.8, 13.0, 14.6, 18.7,
21.1, 26.3.degree. 2.theta. using Cu K.alpha. radiation. In certain
embodiments of the invention, a member of isostructural family 1 of
crystal forms comprising the hydrochloric acid salt of
(-)-O-desmethylvenlafaxine has one, two, three, four, five or six
characteristic X-ray powder diffraction pattern peaks at the
positions of about 5.8, 13.0, 14.6, 18.7, 21.1 and 26.3.degree.
2.theta. using Cu K.alpha. radiation. Solvents for inclusion in the
crystal lattice of a member of the isostructural family 1 of
crystal forms comprising the hydrochloric acid salt of
(-)-O-desmethylvenlafaxine include, but are not limited to,
tetrahydrofuran, ethyl acetate, ethyl ether, acetone, isopropanol,
acetonitrile, ethanol, water, and combinations thereof. Certain
embodiments of the invention provide a member of the isostructural
family 1 of crystal forms comprising the hydrochloric acid salt of
(-)-O-desmethylvenlafaxine that is a desolvated solvate crystal
form. In certain embodiments, a desolvated solvate belonging to
isostructural family 1 may be prepared by the removal of any of the
above-mentioned solvents from the crystal lattice of any solvated
and/or hydrated crystal form member of isostructural family 1. In
certain embodiments, the solvents ethyl acetate, diethyl ether
and/or water are removed from the crystal lattice of Form C (a
crystal form of the HCl salt of (-)-O-desmethylvenlafaxine,
described herein) by way of heating in order to yield a desolvated
solvate member of isostructural family 1. In certain embodiments, a
desolvated solvate that is a member of isostructural family 1 has a
XRPD pattern similar to that of FIG. 54 using Cu K.alpha.
radiation.
[0151] In another embodiment, the invention provides crystal forms
comprising the monohydrochloride salt of (-)-O-desmethylvenlafaxine
belonging to isostructural family 2. In certain embodiments of the
invention, members of isostructural family 2 are selected from the
group consisting of Form E and Form L. In certain embodiments of
the invention, a crystal form that is a member of isostructural
family 2 has characteristic X-ray powder diffraction pattern peaks
at about 11.9, 13.0, 14.4, 18.5, and 20.9.degree. 2.theta. using Cu
K.alpha. radiation. In other embodiments of the invention, a
crystal form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine that is a member of isostructural family
2 has one, two, three, four or five characteristic X-ray powder
diffraction pattern peaks at the positions of about 11.9, 13.0,
14.4, 18.5, and 20.9.degree. 2.theta. using Cu K.alpha. radiation.
Solvents for inclusion in the crystal lattice of a member of the
isostructural family 2 of crystal forms comprising the hydrochloric
acid salt of (-)-O-desmethylvenlafaxine include, but are not
limited to, methyl t-butyl ether, 2-methyl-tetrahydrofuran, water
and combinations thereof. Certain embodiments of the invention
include desolvated solvate crystal forms that are members of
isostructural family 2. In certain embodiments, desolvated solvate
crystal forms that are members of isostructural family 2 are formed
by the desolvation and/or dehydration of a crystal form that is a
member of isostructural family 2.
[0152] In certain embodiments, the present invention provides
amorphous forms comprising (-)-O-desmethylvenlafaxine and salts
thereof, having particular utility for the treatment, prevention or
management of conditions and disorders including, but not limited
to, affective disorders such as depression, bipolar and manic
disorders, attention deficit disorder, attention deficit disorder
with hyperactivity, anxiety disorders, panic disorder, social
anxiety disorder, post traumatic stress disorder, premenstrual
dysphoric disorder, borderline personality disorder, fibromyalgia,
agoraphobia, obsessive compulsive disorder, anorexia and bulimia
nervosa, obesity, weight gain, Gilles de la Tourette Syndrome,
Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease,
epilepsy, narcolepsy, smoking cessation, drug craving, neurally
mediated sexual dysfunction, pain, including chronic and
neuropathic pain, cerebral function disorders, senile dementia,
memory loss, amnesia/amnestic syndrome; disturbances of
consciousness, coma, speech disorders, Lennox syndrome, autism,
hyperkinetic syndrome, schizophrenia, migraine, obesity and weight
gain, incontinence, chronic fatigue syndrome, sleep apnea,
menopausal vasomotor symptoms such as hot flashes, disorders
ameliorated by inhibition of neuronal monoamine uptake, related
disorders, and the mental disorders described in the American
Psychiatric Association's Diagnostic and Statistical Manual of
Mental Disorders, 4.sup.th edition (DSM-IV). Amorphous forms of the
invention can be made following a preparation of
(-)-O-desmethylvenlafaxine, as described herein. Particular
embodiments include the amorphous form comprising either the free
base or a salt of (-)-O-desmethylvenlafaxine. In certain
embodiments, the amorphous forms of the invention are amorphous
forms comprising pharmaceutically acceptable salts of
(-)-O-desmethylvenlafaxine.
[0153] In one embodiment, the present invention provides an
amorphous form of the monohydrochloride salt of
(-)-O-desmethylvenlafaxine
((-)-1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol
monohydrochloride salt). In certain embodiments of the invention,
the amorphous form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine has a thermal gravimetric analysis
thermogram similar to that of FIG. 55. In certain embodiments of
the invention, the amorphous form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine has a modulated differential scanning
calorimetry thermogram similar to that of FIG. 56. In certain
embodiments, when examined by modulated differential scanning
calorimetry according to the methods described herein, the
amorphous form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine has a glass transition temperature of
approximately 24.degree. C. In certain embodiments, the amorphous
form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has an
X-ray powder diffraction pattern similar to that of FIG. 57 using
Cu K.alpha. radiation. Particular embodiments of the amorphous form
of the invention has an X-ray powder diffraction pattern do not
contain sharp diffraction peaks in the range of about 2.5 to
40.0.degree. 2.theta., measured using Cu K.alpha. radiation. In
certain embodiments, the amorphous form of the hydrochloride salt
of (-)-O-desmethylvenlafaxine has a dynamic vapor sorption isotherm
similar to that of FIG. 58. In certain embodiments, when examined
by dynamic vapor sorption according to the methods described
herein, the amorphous form of the hydrochloride salt of the current
invention exhibits a gain in mass of about 36% when increased from
5% to 95% relative humidity, followed by a loss in mass of about
32% when decreased from 95% to 5% relative humidity.
[0154] The amorphous form of the hydrochloride salt of
(-)-O-desmethylvenlafaxine can be made by any method apparent to
those of skill in the art to make the amorphous form based upon the
teachings herein. In particular embodiments of the invention, a
crystal form of a hydrochloride salt of (-)-O-desmethylvenlafaxine
is dissolved in a solvent or solvent mixture, including solvents
such as acetonitrile, isopropanol, ethyl acetate, ethanol,
methanol, or the like, which is then evaporated to yield the
amorphous forms of the invention. In certain embodiments, a solid
form comprising a HCl salt of (-)-O-desmethylvenlafaxine is
dissolved in a suitable solvent or solvents, e.g., water, then
subjected to a freeze drying procedure to yield the amorphous forms
of the invention. In certain embodiments, a hydrate, solvate, or
anhydrous crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine, such as, for example, Form A, is heated
to a temperature above its dehydration, desolvation, or melting
temperature to yield the amorphous forms of the invention.
[0155] Certain embodiments of the invention provide mixtures,
including physical mixtures and/or solid solutions, of solid forms
comprising (-)-O-desmethylvenlafaxine or salts thereof. Certain
embodiments provide mixtures of solid forms comprising the
hydrochloride salt of (-)-O-desmethylvenlafaxine. Certain
embodiments provide mixtures comprising an amorphous form of
(-)-O-desmethylvenlafaxine HCl salt with one or more crystalline
forms of (-)-O-desmethylvenlafaxine HCl salt. Certain embodiments
provide mixtures comprising two or more, three or more, four or
more, five or more, or six or more solid forms of the HCl salt of
(-)-O-desmethylvenlafaxine comprising about 0.1%, 0.5%, 1%, 2%, 3%,
4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%
or 99.9% of an amorphous form of a HCl salt of
(-)-O-desmethylvenlafaxine. Certain embodiments provide mixtures
comprising two or more, three or more, four or more, five or more,
or six or more crystal forms of a HCl salt of
(-)-O-desmethylvenlafaxine, e.g., a mixture comprising Form A and
Form F (-)-O-desmethylvenlafaxine HCl salt. Certain embodiments
provide mixtures comprising two or more, three or more, four or
more, five or more, or six or more crystal forms of the HCl salt of
(-)-O-desmethylvenlafaxine comprising about 0.1%, 0.5%, 1%, 2%, 3%,
4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%
or 99.9% of one form, e.g. Form A, of a HCl salt of
(-)-O-desmethylvenlafaxine. Certain embodiments provide a solid
solution of crystal forms of a HCl salt of
(-)-O-desmethylvenlafaxine, wherein characteristic structural
features (e.g. lattice parameters, XRPD peak positions and/or one
or more solvents of crystallization) comprising two or more, three
or more, four or more, five or more, or six or more crystal forms
which are members of a particular isostructural family of crystal
forms, e.g. isostructural family 1, are exhibited upon analysis of
the mixture.
5.2.3 Compositions
[0156] The present invention provides pharmaceutical compositions
for the treatment, prevention or management of conditions and
disorders including, but not limited to, affective disorders such
as depression, bipolar and manic disorders, attention deficit
disorder, attention deficit disorder with hyperactivity, anxiety
disorders, panic disorder, social anxiety disorder, post traumatic
stress disorder, premenstrual dysphoric disorder, borderline
personality disorder, fibromyalgia, agoraphobia, obsessive
compulsive disorder, anorexia and bulimia nervosa, obesity, weight
gain, Gilles de la Tourette Syndrome, Shy-Drager syndrome,
Alzheimer's disease, Parkinson's disease, epilepsy, narcolepsy,
smoking cessation, drug craving, neurally mediated sexual
dysfunction, pain, including chronic and neuropathic pain, cerebral
function disorders, senile dementia, memory loss, amnesia/amnestic
syndrome; disturbances of consciousness, coma, speech disorders,
Lennox syndrome, autism, hyperkinetic syndrome, schizophrenia,
migraine, obesity and weight gain, incontinence, chronic fatigue
syndrome, sleep apnea, menopausal vasomotor symptoms such as hot
flashes, disorders ameliorated by inhibition of neuronal monoamine
uptake, related disorders, and the mental disorders described in
the American Psychiatric Association's Diagnostic and Statistical
Manual of Mental Disorders, 4.sup.th edition (DSM-IV). The
compositions comprise one or more crystal forms and/or amorphous
forms of the present invention and a pharmaceutically acceptable
diluent, excipient or carrier. In certain embodiments, a
pharmaceutical composition of the invention comprises a pure
crystal or amorphous form of a salt of (-)-O-desmethylvenlafaxine.
For example, a pharmaceutical composition of the invention can
comprise pure Form A monohydrate hydrochloric acid salt of
(-)-O-desmethylvenlafaxine.
[0157] The pharmaceutical compositions for the administration of
the crystalline or amorphous forms of this invention may
conveniently be presented in unit dosage form and may be prepared
by any of the methods well known in the art of pharmacy. All
methods include the step of bringing the active ingredient into
association with the carrier which constitutes one or more
accessory ingredients. In general, the pharmaceutical compositions
are prepared by uniformly and intimately bringing the active
ingredient into association with a liquid carrier or a finely
divided solid carrier or both, and then, if necessary, shaping the
product into the desired formulation. In the pharmaceutical
composition the crystalline or amorphous form is included in an
amount sufficient to produce the desired effect upon the process,
condition or disease to be treated, prevented, or managed.
[0158] Any suitable route of administration can be employed for
providing the patient with a therapeutically and/or
prophylactically effective dose of the active ingredient of the
present invention. For example, this invention comprises single
unit dosage forms suitable for oral, mucosal (e.g., nasal,
sublingual, vaginal, buccal, or rectal), parenteral (e.g.,
subcutaneous, intravenous, bolus injection, intramuscular, or
intraarterial), or transdermal administration to a patient.
Examples of dosage forms include, but are not limited to: tablets;
caplets; capsules, such as hard gelatin or soft elastic gelatin
capsules; cachets; troches; lozenges; dispersions; suppositories;
ointments; cataplasms (poultices); pastes; powders; dressings;
creams; plasters; solutions; patches; aerosols (e.g., nasal sprays
or inhalers); gels; liquid dosage forms suitable for oral or
mucosal administration to a patient, including suspensions (e.g.,
aqueous or non-aqueous liquid suspensions, oil-in-water emulsions,
or a water-in-oil liquid emulsions), solutions, and elixirs; liquid
dosage forms suitable for parenteral administration to a patient;
and sterile solids (e.g., crystalline or amorphous solids) that can
be reconstituted to provide liquid dosage forms suitable for
parenteral administration to a patient.
[0159] In practical use, an active ingredient can be combined in an
intimate admixture with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques. The carrier can
take a wide variety of forms depending on the form of preparation
desired for administration. In preparing the compositions for an
oral dosage form, any of the usual pharmaceutical media can be
employed as carriers, such as, for example, water, glycols, oils,
alcohols, flavoring agents, preservatives, coloring agents, and the
like in the case of oral liquid preparations (such as suspensions,
solutions, and elixirs) or aerosols; or carriers such as starches,
sugars, micro-crystalline cellulose, diluents, granulating agents,
lubricants, binders, and disintegrating agents can be used in the
case of oral solid preparations, preferably without employing the
use of lactose. For example, suitable carriers include powders,
capsules, and tablets, with the solid oral preparations being
preferred over the liquid preparations.
[0160] The composition, shape, and type of dosage forms of the
invention will typically vary depending on their use. For example,
a dosage form used in the acute treatment of a disease may contain
larger amounts of one or more of the active ingredients it
comprises than a dosage form used in the chronic treatment of the
same disease. Similarly, a parenteral dosage form may contain
smaller amounts of one or more of the active ingredients it
comprises than an oral dosage form used to treat the same disease.
These and other ways in which specific dosage forms encompassed by
this invention will vary from one another will be readily apparent
to those skilled in the art. See, e.g., Remington's Pharmaceutical
Sciences, 18th ed., Mack Publishing, Easton, Pa. (1990).
5.2.3.1 Oral Dosage Forms
[0161] Pharmaceutical compositions of the invention that are
suitable for oral administration can be presented as discrete
dosage forms, such as, but are not limited to, tablets, chewable
tablets, caplets, capsules, and liquids (e.g., flavored syrups).
Such dosage forms contain predetermined amounts of active
ingredients, and may be prepared by methods of pharmacy well known
to those skilled in the art. See generally, Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton, Pa.
(1990).
[0162] Typical oral dosage forms of the invention are prepared by
combining the active ingredients in an intimate admixture with at
least one excipient according to conventional pharmaceutical
compounding techniques. Excipients can take a wide variety of forms
depending on the form of preparation desired for
administration.
[0163] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or nonaqueous techniques. Such dosage
forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0164] Disintegrants or lubricants can be used in pharmaceutical
compositions and dosage forms of the invention. Production of
pharmaceutical compositions or dosage forms in accordance with the
present invention may require, in addition to the therapeutic drug
ingredients, excipients or additives including, but not limited to,
diluents, binders, lubricants, disintegrants, colorants, flavors,
sweetening agents and the like or mixtures thereof. By the
incorporation of these and other additives, a variety of dosage
forms (e.g., tablets, capsules, caplets, troches and the like) may
be made. These include, for example, hard gelatin capsules,
caplets, sugar-coated tablets, enteric-coated tablets to delay
action, multiple compressed tablets, prolonged-action tablets,
tablets for solution, effervescent tablets, buccal and sublingual
tablets, troches and the like.
[0165] Hence, unit dose forms or dosage formulation of a
pharmaceutical composition of the present invention, such as a
troche, a tablet or a capsule, may be formed by combining a desired
amount of each of the active ingredients with one or more
pharmaceutically compatible or acceptable excipients, as described
below, in pharmaceutically compatible amounts to yield a unit dose
dosage formulation the desired amount of each active ingredient.
The dose form or dosage formulation may be formed by methods well
known in the art.
[0166] Tablets are often a preferred dosage form because of the
advantages afforded both to the patient (e.g., accuracy of dosage,
compactness, portability, blandness of taste as well as ease of
administration) and to the manufacturer (e.g., simplicity and
economy of preparation, stability as well as convenience in
packaging, shipping and dispensing). Tablets are solid
pharmaceutical dosage forms containing therapeutic drug substances
with or without suitable additives.
[0167] Tablets are typically made by molding, by compression or by
generally accepted tablet forming methods. Accordingly, compressed
tablets are usually prepared by large-scale production methods
while molded tablets often involve small-scale operations. For
example, there are three general methods of tablet preparation: (1)
the wet-granulation method; (2) the dry-granulation method; and (3)
direct compression. These methods are well known to those skilled
in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th
and 18th eds., Mack Publishing Co., Easton, Pa. (1980 and 1990).
See also U.S. Pharmacopeia XXI, U.S. Pharmacopeial Convention,
Inc., Rockville, Md. (1985).
[0168] Various tablet formulations may be made in accordance with
the present invention. These include tablet dosage forms such as
sugar-coated tablets, film-coated tablets, enteric-coated tablets,
multiple-compressed tablets, prolonged action tablets and the like.
Sugar-coated tablets (SCT) are compressed tablets containing a
sugar coating. Such coatings may be colored and are beneficial in
covering up drug substances possessing objectionable tastes or
odors and in protecting materials sensitive to oxidation.
Film-coated tablets (FCT) are compressed tablets which are covered
with a thin layer or film of a water-soluble material. A number of
polymeric substances with film-forming properties may be used. The
film coating imparts the same general characteristics as sugar
coating with the added advantage of a greatly reduced time period
required for the coating operation. Enteric-coated tablets are also
suitable for use in the present invention. Enteric-coated tablets
(ECT) are compressed tablets coated with substances that resist
dissolution in gastric fluid but disintegrate in the intestine.
Enteric coating can be used for tablets containing drug substances
which are inactivated or destroyed in the stomach, for those which
irritate the mucosa or as a means of delayed release of the
medication.
[0169] Multiple compressed tablets (MCT) are compressed tablets
made by more than one compression cycle, such as layered tablets or
press-coated tablets. Layered tablets are prepared by compressing
additional tablet granulation on a previously compressed
granulation. The operation may be repeated to produce multilayered
tablets of two, three or more layers. Typically, special tablet
presses are required to make layered tablets. See, for example,
U.S. Pat. No. 5,213,738, incorporated herein in its entirety by
reference thereto.
[0170] Press-coated tablets are another form of multiple compressed
tablets. Such tablets, also referred to as dry-coated tablets, are
prepared by feeding previously compressed tablets into a tableting
machine and compressing another granulation layer around the
preformed tablets. These tablets have all the advantages of
compressed tablets, i.e., slotting, monogramming, speed of
disintegration, etc., while retaining the attributes of sugar
coated tablets in masking the taste of the drug substance in the
core tablet. Press-coated tablets can also be used to separate
incompatible drug substances. Further, they can be used to provide
an enteric coating to the core tablets. Both types of tablets
(i.e., layered tablets and press-coated tablets) may be used, for
example, in the design of prolonged-action dosage forms of the
present invention.
[0171] Pharmaceutical compositions or unit dosage forms of the
present invention in the form of prolonged-action tablets may
comprise compressed tablets formulated to release the drug
substance in a manner to provide medication over a period of time.
There are a number of tablet types that include delayed-action
tablets in which the release of the drug substance is prevented for
an interval of time after administration or until certain
physiological conditions exist. Repeat action tablets may be formed
that periodically release a complete dose of the drug substance to
the gastrointestinal fluids. Also, extended release tablets that
continuously release increments of the contained drug substance to
the gastrointestinal fluids may be formed.
[0172] In order for medicinal substances or therapeutic ingredients
of the present invention, with or without excipients, to be made
into solid dosage forms (e.g., tablets) with pressure, using
available equipment, it is necessary that the material, either in
crystalline or amorphous form, possess a number of physical
characteristics. These characteristics can include, for example,
the ability to flow freely, as a powder to cohere upon compaction,
and to be easily released from tooling. Since many materials have
none or only some of these properties, methods of tablet
formulation and preparation have been developed to impart these
desirable characteristics to the material which is to be compressed
into a tablet or similar dosage form.
[0173] As noted, in addition to the drugs or therapeutic
ingredients, tablets and similar dosage forms may contain a number
of materials referred to as excipients or additives. These
additives are classified according to the role they play in the
formulation of the dosage form such as a tablet, a caplet, a
capsule, a troche or the like. One group of additives include, but
are not limited to, binders, diluents (fillers), disintegrants,
lubricants, and surfactants. In one embodiment, the diluent,
binder, disintegrant, and lubricant are not the same.
[0174] A binder is used to provide a free-flowing powder from the
mix of tablet ingredients so that the material will flow when used
on a tablet machine. The binder also provides a cohesiveness to the
tablet. Too little binder will give flow problems and yield tablets
that do not maintain their integrity, while too much can adversely
affect the release (dissolution rate) of the drugs or active
ingredients from the tablet. Thus, a sufficient amount of binder
should be incorporated into the tablet to provide a free-flowing
mix of the tablet ingredients without adversely affecting the
dissolution rate of the drug ingredients from the tablet. With
lower dose tablets, the need for good compressibility can be
eliminated to a certain extent by the use of suitable diluting
excipients called compression aids. The amount of binder used
varies upon the type of formulation and mode of administration, and
is readily discernible to those of ordinary skill in the art.
[0175] Binders suitable for use with dosage formulations made in
accordance with the present invention include, but are not limited
to, corn starch, potato starch, or other starches, gelatin, natural
and synthetic gums such as acacia, sodium alginate, alginic acid,
other alginates, powdered tragacanth, guar gum, cellulose and its
derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone (povidone), methyl cellulose, pre-gelatinized
starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906,
2910), microcrystalline cellulose or mixtures thereof. Suitable
forms of microcrystalline cellulose can include, for example, the
materials sold as AVICEL-PH-101, AVICEL-PH-103 and AVICEL-PH-105
(available from FMC Corporation, American Viscose Division, Avicel
Sales, Marcus Hook, Pa., U.S.A.).
[0176] Fillers or diluents are used to give the powder (e.g., in
the tablet or capsule) bulk so that an acceptable size tablet,
capsule or other desirable dosage form is produced. Typically,
therapeutic ingredients are formed in a convenient dosage form of
suitable size by the incorporation of a diluent therewith. As with
the binder, binding of the drug(s) to the filler may occur and
affect bioavailability. Consequently, a sufficient amount of filler
should be used to achieve a desired dilution ratio without
detrimentally affecting release of the drug ingredients from the
dosage form containing the filler. Further, a filler that is
physically and chemically compatible with the therapeutic
ingredient(s) of the dosage form should be used. The amount of
filler used varies upon the type of formulation and mode of
administration, and is readily discernible to those of ordinary
skill in the art. Examples of fillers include, but are not limited
to, lactose, glucose, sucrose, fructose, talc, calcium carbonate
(e.g., granules or powder), microcrystalline cellulose, powdered
cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol,
starch, pre-gelatinized starch, or mixtures thereof.
[0177] Disintegrants are used to cause the dose form (e.g., tablet)
to disintegrate when exposed to an aqueous environment. Too much of
a disintegrant will produce tablets which may disintegrate in the
bottle due to atmospheric moisture. Too little may be insufficient
for disintegration to occur and may thus alter the rate and extent
of release of drug(s) or active ingredient(s) from the dosage form.
Thus, a sufficient amount of disintegrant that is neither too
little nor too much to detrimentally alter the release of the drug
ingredients should be used to form the dosage forms made according
to the present invention. The amount of disintegrant used varies
based upon the type of formulation and mode of administration, and
is readily discernible to the skilled artisan. Examples of
disintegrants include, but are not limited to, agar-agar, alginic
acid, calcium carbonate, microcrystalline cellulose, croscarmellose
sodium, crospovidone, polacrilin potassium, sodium starch
glycolate, potato or tapioca starch, other starches,
pre-gelatinized starch, clays, other algins, other celluloses,
gums, or mixtures thereof.
[0178] When a dose form is desired that dissolves fairly rapidly
upon administration to the subject, e.g., in the subject's stomach,
a super disintegrant can be used, such as, but not limited to,
croscarmellose sodium or sodium starch glycolate. The term "super
disintegrant," as used herein, means a disintegrant that results in
rapid disintegration of drug or active ingredient in the stomach
after oral administration. Use of a super disintegrant can
facilitate the rapid absorption of drug or active ingredient(s)
which may result in a more rapid onset of action.
[0179] With regard to tablet dosage forms, adhesion of the dosage
form ingredients to the punches of manufacturing machines (e.g., a
tableting machine) must be avoided. For example, when drug
accumulates on the punch surfaces, the tablet surfaces may become
pitted and therefore unacceptable. Also, sticking of drug or
excipients in this way requires unnecessarily high ejection forces
when removing the tablet from the die. Excessive ejection forces
may lead to a high breakage rate and increase the cost of
production not to mention excessive wear and tear on the dies. In
practice, it is possible to reduce sticking by wet-massing or by
the use of high levels of lubricants, e.g., magnesium stearate. In
addition, selection of drug salts and/or excipients with good
anti-adhesion properties can also minimize these problems.
[0180] As noted, the lubricant is used to enhance the flow of the
tableting powder mix to the tablet machine and to prevent sticking
of the tablet in the die after the tablet is compressed. Too little
lubricant will not permit satisfactory tablets to be made and too
much may produce a tablet with a water-impervious hydrophobic
coating, which can form because lubricants are usually hydrophobic
materials such as stearic acid, magnesium stearate, calcium
stearate and the like. Further, a water-impervious hydrophobic
coating can inhibit disintegration of the tablet and dissolution of
the drug ingredient(s). Thus, a sufficient amount of lubricant
should be used that readily allows release of the compressed tablet
from the die without forming a water-impervious hydrophobic coating
that detrimentally interferes with the desired disintegration
and/or dissolution of the drug ingredient(s).
[0181] Examples of suitable lubricants for use with the present
invention include, but are not limited to, calcium stearate,
magnesium stearate, mineral oil, light mineral oil, glycerin,
sorbitol, mannitol, polyethylene glycol, other glycols, stearic
acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil
(e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive
oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl
laurate, agar, or mixtures thereof. Additional lubricants include,
for example, a syloid silica gel (AEROSIL 200, manufactured by W.R.
Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic
silica (marketed by Deaussa Co. of Plano, Tex.), CAB-O-SIL (a
pyrogenic silicon dioxide product sold by Cabot Co. of Boston,
Mass.) or mixtures thereof. 1001821 Surfactants are used in dosage
forms to improve the wetting characteristics and/or to enhance
dissolution, and are particularly useful in pharmaceutical
compositions or dosage forms containing poorly soluble or insoluble
drug(s) or active ingredients. Examples of surfactants include, but
are not limited to, polyoxyethylene sorbitan fatty acid esters,
such as those commercially available as TWEENs (e.g. Tween 20 and
Tween 80), polyethylene glycols, polyoxyethylene stearates,
polyvinyl alcohol, polyvinylpyrrolidone,
poly(oxyethylene)/poly(oxypropylene) block co-polymers such as
poloxamers (e.g., commercially available as PLURONICs), and
tetrafunctional block copolymers derived from sequential addition
of propylene oxide and ethylene oxide to ethylenediamine, such as
polyxamines (e.g., commercially as TETRONICs (BASF)), dextran,
lecithin, dialkylesters of sodium sulfosuccinic acid, such as
Aerosol OT, sodium lauryl sulfate, alkyl aryl polyether sulfonates
or alcohols, such as TRITON X-200 or tyloxapol,
p-isononylphenoxypoly (glycidol) (e.g. Olin-10G or Surfactant 10-G
(Olin Chemicals), or mixtures thereof. Other pharmaceutically
acceptable surfactants are well known in the art, and are described
in detail in the Handbook of Pharmaceutical Excipients, 4.sup.th
ed., Pharmaceutical Press, London, UK and American Pharmaceutical
Association, Washington, D.C. (2003).
[0182] Other classes of additives for use with the pharmaceutical
compositions or dosage forms of the present invention include, but
are not limited to, anti-caking or antiadherent agents,
antimicrobial preservatives, coating agents, colorants, desiccants,
flavors and perfumes, plasticizers, viscosity increasing agents,
sweeteners, buffering agents, humectants and the like.
[0183] Examples of anti-caking agents include, but are not limited
to, calcium silicate, magnesium silicate, silicon dioxide,
colloidal silicon dioxide, talc, or mixtures thereof.
[0184] Examples of antimicrobial preservatives include, but are not
limited to, benzalkonium chloride solution, benzethonium chloride,
benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium
chloride, chlorobutanol, cresol, dehydroacetic acid, ethylparaben,
methylparaben, hydroxyphenyl, phenylethyl alcohol, phenylmercuric
acetate, phenylmercuric nitrate, potassium sorbate, propylparaben,
sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic
acid, thimersol, thymol, or mixtures thereof.
[0185] Examples of colorants for use with the present invention
include, but are not limited to, pharmaceutically acceptable dyes
and lakes, caramel, red ferric oxide, yellow ferric oxide or
mixtures thereof. Examples of desiccants include, but are not
limited to, calcium chloride, calcium sulfate, silica gel or
mixtures thereof.
[0186] Flavors that may be used include, but are not limited to,
acacia, tragacanth, almond oil, anethole, anise oil, benzaldehyde,
caraway, caraway oil, cardamom oil, cardamom seed, compound
cardamom tincture, cherry juice, cinnamon, cinnamon oil, clove oil,
cocoa, coriander oil, eriodictyon, eriodictyon fluidextract, ethyl
acetate, ethyl vanillin, eucalyptus oil, fennel oil, glycyrrhiza,
pure glycyrrhiza extract, glycyrrhiza fluidextract, lavender oil,
lemon oil, menthol, methyl salicylate, monosodium glutamate, nutmeg
oil, orange flower oil, orange flower water, orange oil, sweet
orange peel tincture, compound orange spirit, peppermint,
peppermint oil, peppermint spirit, pine needle oil, rose oil,
stronger rose water, spearmint, spearmint oil, thymol, tolu balsam
tincture, vanilla, vanilla tincture, and vanillin or mixture
thereof.
[0187] Examples of sweetening agents include, but are not limited
to, aspartame, dextrates, mannitol, saccharin, saccharin calcium,
saccharin sodium, acesulfame potassium, sucralose (splenda.RTM.
brand), sorbitol, sorbitol solution, or mixtures thereof.
[0188] Exemplary plasticizers for use with the present invention
include, but are not limited to, castor oil, diacetylated
monoglycerides, diethyl phthalate, glycerin, mono-and di-acetylated
monoglycerides, polyethylene glycol, propylene glycol, and
triacetin or mixtures thereof. Suitable viscosity increasing agents
include, but are not limited to, acacia, agar, alamic acid,
aluminum monostearate, bentonite, bentonite magma, carbomer 934,
carboxymethylcellulose calcium, carboxymethylcellulose sodium,
carboxymethylcellulose sodium 12, carrageenan, cellulose,
microcrystalline cellulose, gelatin, guar gum, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose
(Nos. 2208; 2906; 2910), magnesium aluminum silicate,
methylcellulose, pectin, polyvinyl alcohol, povidone, silica gel,
colloidal silicon dioxide, sodium alginate, tragacanth and xanthan
gum or mixtures thereof.
[0189] Buffering agents that may be used in the present invention
include, but are not limited to, magnesium hydroxide, aluminum
hydroxide and the like, or mixtures thereof. Examples of humectants
include, but are not limited to, glycerol, other humectants or
mixtures thereof.
[0190] The dosage forms of the present invention may further
include one or more of the following: (1) dissolution retarding
agents, such as paraffin; (2) absorption accelerators, such as
quaternary ammonium compounds; (3) wetting agents, such as, for
example, cetyl alcohol and glycerol monostearate; (4) absorbents,
such as kaolin and bentonite clay; (5) antioxidants, such as water
soluble antioxidants (e.g., ascorbic acid, cysteine hydrochloride,
sodium bisulfate, sodium metabisulfate, sodium sulfite and the
like), oil soluble antioxidants (e.g., ascorbyl palmitate,
hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin,
propyl gallate, alpha-tocopherol and the like); and (6) metal
chelating agents, such as citric acid, ethylenediamine tetracetic
acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the
like.
[0191] Dosage forms of the present invention, such as a tablet or
caplet, may optionally be coated. Inert coating agents typically
comprise an inert film-forming agent dispersed in a suitable
solvent, and may further comprise other pharmaceutically acceptable
adjuvants, such as colorants and plasticizers. Suitable inert
coating agents, and methods for coating, are well known in the art,
including without limitation aqueous or non-aqueous film coating
techniques or microencapsulation. Examples of film-forming or
coating agents include, but are not limited to, gelatin,
pharmaceutical glaze, shellac, sucrose, titanium dioxide, carnauba
wax, microcrystalline wax, celluloses, such as methylcellulose,
hydroxymethyl cellulose, carboxymethycellulose, cellulose acetate
phthalate, hydroxypropyl methylcellulose (e.g., Nos.: 2208, 2906,
2910), hydroxypropyl cellulose, hydroxypropyl methyl cellulose
phthalate (e.g., Nos.: 200731, 220824), hydroxyethylcellulose,
methylhydroxyethylcellulose, ethylcellulose which may optionally be
cross-linked, and sodium carboxymethyl cellulose; vinyls, such as
polyvinyl pyrrolidione, polyvinyl acetate phthalate; glycols, such
as polyethylene glycols; acrylics, such as dimethylaminoethyl
methacrylate-methacrylate acid ester copolymer, and
ethylacrylate-methylmethacrylate copolymer; and other carbohydrate
polymers, such as maltodextrins, and polydextrose, or mixtures
thereof. The amount of coating agent and the carrier vehicle
(aqueous or non-aqueous) used varies upon the type of formulation
and mode of administration, and is readily discernible to those of
ordinary skill in the art.
[0192] A coating of a film forming polymer may optionally be
applied to a tablet or caplet (e.g., a capsule shaped tablet) in
accordance with the present invention by using one of several types
of equipment such as a conventional coating pan, Accelacota,
High-Cola or Worster air suspension column. Such equipment
typically has an exhaust-system to remove dust and solvent or water
vapors to facilitate quick drying. Spray guns or other suitable
atomizing equipment may be introduced into the coating pans to
provide spray patterns conducive to rapid and uniform coverage of
the tablet bed. Normally, heated or cold drying air is introduced
over the tablet bed in a continuous or alternate fashion with a
spray cycle to expedite drying of the film coating solution.
[0193] The coating solution may be sprayed by using positive
pneumatic displacement or peristaltic pump systems in a continuous
or intermittent spray-dry cycle. The particular type of spray
application is selected depending upon the drying efficiency of the
coating pan. In most cases, the coating material is sprayed until
the tablets are uniformly coated to the desired thickness and the
desired appearance of the tablet is achieved. Many different types
of coatings may be applied such as enteric, slow release coatings
or rapidly dissolving type coatings for fast acting tablets.
Preferably, rapidly dissolving type coatings are used to permit
more rapid release of the active ingredients, resulting in hastened
onset. The thickness of the coating of the film forming polymer
applied to a tablet, for example, may vary. However, it is
preferred that the thickness simulate the appearance, feel (tactile
and mouth feel) and function of a gelatin capsule. Where more rapid
or delayed release of the therapeutic agent(s) is desired, one
skilled in the art would easily recognize the film type and
thickness, if any, to use based on characteristics such as desired
blood levels of active ingredient, rate of release, solubility of
active ingredient, and desired performance of the dosage form.
[0194] A number of suitable film forming agents for use in coating
a final dosage form, such as tablets include, for example,
methylcellulose, hydroxypropyl methyl cellulose (PHARMACOAT 606 6
cps), polyvinylpyrrolidone (povidone), ethylcellulose (ETHOCEL 10
cps), various derivatives of methacrylic acids and methacrylic acid
esters, cellulose acetate phthalate or mixtures thereof.
[0195] The method of preparation and the excipients or additives to
be incorporated into dosage form (such as a tablet or caplet) are
selected in order to give the tablet formulation the desirable
physical characteristics while allowing for ease of manufacture
(e.g., the rapid compression of tablets). After manufacture, the
dose form preferably should have a number of additional attributes,
for example, for tablets, such attributes include appearance,
hardness, disintegration ability and uniformity, which are
influenced both by the method of preparation and by the additives
present in the tablet formulation.
[0196] Further, it is noted that tablets or other dosage forms of
the pharmaceutical compositions of the invention should retain
their original size, shape, weight and color under normal handling
and storage conditions throughout their shelf life. Thus, for
example, excessive powder or solid particles at the bottom of the
container, cracks or chips on the face of a tablet, or appearance
of crystals on the surface of tablets or on container walls are
indicative of physical instability of uncoated tablets. Hence, the
effect of mild, uniform and reproducible shaking and tumbling of
tablets should be undertaken to insure that the tablets have
sufficient physical stability. Tablet hardness can be determined by
commercially available hardness testers. In addition, the in vitro
availability of the active ingredients should not change
appreciably with time.
[0197] The tablets, and other dosage forms of the pharmaceutical
compositions of the present invention, such as dragees, capsules,
pills and granules, may optionally be scored or prepared with
coatings and shells, such as enteric coatings and other coatings
well known in the pharmaceutical formulating art.
[0198] In one embodiment, it is desirable to use a lubricant in
pharmaceutical composition and dosage forms of the invention that
include an ARB that is poorly soluble or insoluble in water.
5.2.3.2 Parenteral Dosage Forms
[0199] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0200] Suitable vehicles that can be used to provide parenteral
dosage forms of the invention are well known to those skilled in
the art. Examples include, but are not limited to: Water for
Injection USP; aqueous vehicles such as, but not limited to, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and Lactated Ringer's
Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles such as, but not limited to, corn oil,
cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl benzoate.
[0201] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein (i.e., the compounds of this
invention) can also be incorporated into the parenteral dosage
forms of the invention.
5.2.3.3 Transdermal, Topical and Mucosal Dosage Forms
[0202] Transdermal, topical, and mucosal dosage forms of the
invention include, but are not limited to, ophthalmic solutions,
sprays, aerosols, creams, lotions, ointments, gels, solutions,
emulsions, suspensions, or other forms known to one of skill in the
art. See, e.g., Remington's Pharmaceutical Sciences, 16.sup.th and
18.sup.th eds., Mack Publishing, Easton, Pa. (1980 & 1990); and
Introduction to Pharmaceutical Dosage Forms, 4.sup.th ed., Lea
& Febiger, Philadelphia (1985). Transdermal dosage forms
include "reservoir type" or "matrix type" patches, which can be
applied to the skin and worn for a specific period of time to
permit the penetration of a desired amount of active
ingredients.
[0203] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal, topical, and
mucosal dosage forms encompassed by this invention are well known
to those skilled in the pharmaceutical arts, and depend on the
particular tissue to which a given pharmaceutical composition or
dosage form will be applied.
[0204] Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients of the invention. For example,
penetration enhancers can be used to assist in delivering the
active ingredients to the tissue.
[0205] The pH of a pharmaceutical composition or dosage form, or of
the tissue to which the pharmaceutical composition or dosage form
is applied, may also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery-enhancing or
penetration-enhancing agent. Different crystal or amorphous forms
of the active ingredients can be used to further adjust the
properties of the resulting composition.
5.2.3.4 Compositions with Enhanced Stability
[0206] The suitability of a particular excipient may also depend on
the specific active ingredients in the dosage form. For example,
the decomposition of some active ingredients may be accelerated by
some excipients such as lactose, or when exposed to water. Active
ingredients that comprise primary or secondary amines are
particularly susceptible to such accelerated decomposition. This
invention encompasses pharmaceutical compositions and dosage forms
that contain little, if any, lactose other mono- or di-saccharides.
As used herein, the term "lactose-free" means that the amount of
lactose present, if any, is insufficient to substantially increase
the degradation rate of an active ingredient.
[0207] Lactose-free compositions of the invention can comprise
excipients that are well known in the art and are listed, for
example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In general,
lactose-free compositions comprise active ingredients, a
binder/filler, and a lubricant in pharmaceutically compatible and
pharmaceutically acceptable amounts. Preferred lactose-free dosage
forms comprise active ingredients, microcrystalline cellulose,
pre-gelatinized starch, and magnesium stearate.
[0208] This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Carstensen, Drug
Stability: Principles & Practice, 2.sup.nd ed., Marcel Dekker,
New York, N.Y., pp. 379-80 (1995). In effect, water and heat
accelerate the decomposition of some compounds. Thus, the effect of
water on a formulation can be of great significance since moisture
and/or humidity are commonly encountered during manufacture,
handling, packaging, storage, shipment, and use of
formulations.
[0209] Anhydrous pharmaceutical compositions and dosage forms of
the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine are preferably anhydrous if substantial contact
with moisture and/or humidity during manufacturing, packaging,
and/or storage is expected.
[0210] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are preferably packaged using
materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils,
plastics, unit dose containers (e.g., vials), blister packs, and
strip packs.
[0211] The invention further encompasses pharmaceutical
compositions and dosage forms that comprise one or more compounds
that reduce the rate by which an active ingredient will decompose.
Such compounds, which are referred to herein as "stabilizers,"
include, but are not limited to, antioxidants such as ascorbic
acid, pH buffers, or salt buffers.
[0212] Like the amounts and types of excipients, the amounts and
specific types of active ingredients in a dosage form may differ
depending on factors such as, but not limited to, the route by
which it is to be administered to patients.
5.2.3.5 Delayed Release Dosage Forms
[0213] Active ingredients of the invention can be administered by
controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533,
5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556,
and 5,733,566, each of which is incorporated herein by reference.
Such dosage forms can be used to provide slow or controlled-release
of one or more active ingredients using, for example,
hydropropylmethyl cellulose, eudragit L-100, carnauba wax,
magnesium stearate, methocel K4M CR, Surelease, Kollidon SR, other
polymer matrices, gels, permeable membranes, osmotic systems,
multilayer coatings, microparticles, liposomes, microspheres, or a
combination thereof to provide the desired release profile in
varying proportions. Suitable controlled-release formulations known
to those of ordinary skill in the art, including those described
herein, can be readily selected for use with the compounds of this
invention. The invention thus encompasses single unit dosage forms
suitable for oral administration such as, but not limited to,
tablets, capsules, gelcaps, and caplets that are adapted for
controlled-release.
[0214] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0215] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release other amounts of drug to maintain this level of
therapeutic or prophylactic effect over an extended period of time.
In order to maintain this constant level of drug in the body, the
drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds. Certain embodiments of the invention provide
delayed-release formulations comprising (-)-O-desmethylvenlafaxine,
including salts thereof. In certain embodiments, the
delayed-release formulation comprising (-)-O-desmethylvenlafaxine,
including salts thereof, has an advantageous, e.g., slowed,
dissolution profile of the (-)-O-desmethylvenlafaxine, including
salts and derivatives thereof. In certain embodiments, the
formulation comprises the ingredients as described in the
"Formulation of Premix" and "Final Formulation" as provided in the
Examples section, infra.
5.2.3.6 Kits
[0216] In some cases, active ingredients of the invention are
preferably not administered to a patient at the same time or by the
same route of administration. This invention therefore encompasses
kits which, when used by the medical practitioner, can simplify the
administration of appropriate amounts of active ingredients to a
patient.
[0217] A typical kit of the invention comprises a single unit
dosage form of the compounds of this invention, or a
pharmaceutically acceptable salt, prodrug, solvate, hydrate,
clathrate or stereoisomer thereof, and a single unit dosage form of
another agent that may be used in combination with the compounds of
this invention. Kits of the invention can further comprise devices
that are used to administer the active ingredients. Examples of
such devices include, but are not limited to, syringes, drip bags,
patches, and inhalers.
[0218] Kits of the invention can further comprise pharmaceutically
acceptable vehicles that can be used to administer one or more
active ingredients. For example, if an active ingredient is
provided in a solid form that must be reconstituted for parenteral
administration, the kit can comprise a sealed container of a
suitable vehicle in which the active ingredient can be dissolved to
form a particulate-free sterile solution that is suitable for
parenteral administration. Examples of pharmaceutically acceptable
vehicles include, but are not limited to: Water for Injection USP;
aqueous vehicles such as, but not limited to, Sodium Chloride
Injection, Ringer's Injection, Dextrose Injection, Dextrose and
Sodium Chloride Injection, and Lactated Ringer's Injection;
water-miscible vehicles such as, but not limited to, ethyl alcohol,
polyethylene glycol, and polypropylene glycol; and non-aqueous
vehicles such as, but not limited to, corn oil, cottonseed oil,
peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and
benzyl benzoate.
[0219] The invention is further defined by reference to the
following non-limiting examples. It will be apparent to those
skilled in the art that many modifications, both to materials and
methods, can be practiced without departing from the spirit and
scope of this invention.
[0220] The pharmaceutical composition and method of the present
invention may further comprise other therapeutically active
compounds as noted herein which are usually applied in the
treatment, prevention or management of the above mentioned
pathological conditions.
5.2.4 Methods of Use
[0221] In certain embodiments, utilizing optically pure or
substantially optically pure (-)-O-desmethylvenlafaxine or salts
thereof in the treatment, prevention and/or management of the
conditions described herein results in clearer dose-related
definitions of efficacy, diminished adverse effects, and
accordingly an improved therapeutic index as compared to
venlafaxine itself.
[0222] In certain embodiments, the present invention provides
methods of treating, preventing or managing one or more diseases,
disorders or conditions by administering a therapeutic and/or
prophylactic dose of a solid form comprising
(-)-O-desmethylvenlafaxine described herein, e.g. a crystal form
comprising a hydrochloride salt of (-)-O-desmethylvenlafaxine, to a
subject, e.g. a human, in need of such treatment, prevention and/or
management, wherein said diseases, disorders or conditions include,
but are not limited to, affective disorders such as depression,
bipolar and manic disorders, attention deficit disorder, attention
deficit disorder with hyperactivity, anxiety disorders, panic
disorder, social anxiety disorder, post traumatic stress disorder,
premenstrual dysphoric disorder, borderline personality disorder,
fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia
and bulimia nervosa, obesity, weight gain, Gilles de la Tourette
Syndrome, Shy-Drager syndrome, Alzheimer's disease, Parkinson's
disease, epilepsy, narcolepsy, smoking cessation, drug craving,
neurally mediated sexual dysfunction, pain, including chronic and
neuropathic pain, cerebral function disorders, senile dementia,
memory loss, amnesia/amnestic syndrome, disturbances of
consciousness, coma, speech disorders, Lennox syndrome, autism,
hyperkinetic syndrome, schizophrenia, migraine, obesity and weight
gain, incontinence, chronic fatigue syndrome, sleep apnea,
menopausal vasomotor symptoms such as hot flashes, disorders
ameliorated by inhibition of neuronal monoamine uptake, related
disorders, and the mental disorders described in the American
Psychiatric Association's Diagnostic and Statistical Manual of
Mental Disorders, 4.sup.th edition (DSM-IV).
[0223] The magnitude of a prophylactic or therapeutic dose of
(-)-O-desmethylvenlafaxine (herein also referred to as an "active
ingredient"), in the acute or chronic management of a disease, will
vary with the severity of the condition to be treated and the route
of administration. The dose, and in certain embodiments the dose
frequency, will also vary according to age, body weight, response,
and the past medical history of the individual patient. In certain
embodiments of the invention, the recommended daily dose range for
the conditions described herein lie within the range of from about
10 mg to about 1000 mg per day. In certain embodiments, the
recommended daily dose is given as a single once-a-day dose, e.g.
in the morning. In certain embodiments, the recommended daily dose
is given as divided doses throughout the day taken with food. In
certain embodiments, a daily dose range is from about 50 mg to
about 500 mg per day. In certain embodiments, a daily dose range is
between about 75 mg and about 300 mg per day. In certain
embodiments, a daily dose range is from about 50 mg to about 200 mg
per day. In certain embodiments, a daily dose range is from about
25 mg to about 250 mg per day. In managing the patient, the therapy
should be initiated at a lower dose, perhaps about 50 mg to about
75 mg, and increased if necessary up to about 250 mg to about 325
mg per day as either a single dose or divided doses, depending on
the patient's global response. If a dosage is increased, it is
preferably done in intervals of about 75 mg separated by at least 4
days.
[0224] Because elimination of (-)-O-desmethylvenlafaxine from the
bloodstream is dependant on renal and liver function, it is
recommended that the total daily dose be reduced by at least 50% in
patients with moderate hepatic impairment, and that it be reduced
by 25% in patients with mild to moderate renal impairment. For
patients undergoing hemodialysis, it is recommended that the total
daily dose be reduced by 5% and that the dose be withheld until the
dialysis treatment is completed. Because some adverse reactions
have been reported for patients who took venlafaxine concurrently
with, or shortly after, a monoamine oxidase inhibitor, it is
recommended that (-)-O-desmethylvenlafaxine not be administered to
patients currently taking such inhibitors. In general, the
concurrent administration of the compounds of this invention with
other drugs, particularly other serotonin uptake inhibitors, should
be done with care. See, e.g., von Moltke, et al. Biol. Psychiat.,
41:377-380 (1997); and Sinclair, J. et al. Rev. Contemp.
Pharmacother, 9:333-344 (1998).
[0225] The various terms "said amount being sufficient to alleviate
the affective disorder," "said amount being sufficient to alleviate
depression," "said amount being sufficient to alleviate attention
deficit disorder," "said amount being sufficient to alleviate an
obsessive-compulsive disorder," "said amount being sufficient to
prevent or alleviate substance abuse," "said amount being
sufficient to prevent or alleviate pre-menstrual syndrome," "said
amount being sufficient to prevent or alleviate anxiety," "said
amount being sufficient to prevent or alleviate an eating
disorder," "said amount being sufficient to prevent or alleviate or
prevent migraine," "said amount being sufficient to alleviate
Parkinson's disease," "said amount being sufficient to alleviate
epilepsy," "said amount being sufficient to alleviate obesity or
weight gain," "an amount sufficient to achieve weight loss," "said
amount being sufficient to bring about weight reduction in a
human," "said amount being sufficient to alleviate pain," "said
amount being sufficient to alleviate dementia," "said amount
sufficient to alleviate said disorders ameliorated by inhibition of
neuronal monoamine reuptake," "said amount is sufficient to
alleviate cerebral function disorders," "said amount being
sufficient to alleviate a mental disorder," wherein said disorders
are selected from the group consisting of senile dementia,
Alzheimer's type dementia, memory loss, amnesia/amnestic syndrome,
disturbance of consciousness, coma, lowering of attention, speech
disorders, Parkinson's disease, Lennox syndrome, autism,
hyperkinetic syndrome, schizophrenia, and cerebrovascular diseases,
such as cerebral infarction, cerebral bleeding, cerebral
arteriosclerosis, cerebral venous thrombosis, head injuries, mental
disorders including those described in the American Psychiatric
Association's Diagnostic and Statistical Manual of Mental
Disorders, 4.sup.th edition (DSM-IV), and the like, "said amount
being sufficient to treat, prevent or manage incontinence" wherein
said incontinence includes but is not limited to fecal, stress,
urinary, urinary exertional, urge, reflex, passive and overflow
incontinence, are encompassed by the above described dosage amounts
and dose frequency schedule. Similarly, amounts sufficient to
alleviate each of the above disorders but insufficient to cause
adverse effects associated with venlafaxine are also encompassed by
the above described dosage amounts and dose frequency schedule.
[0226] The invention is further defined by reference to the
following non-limiting examples. It will be apparent to those
skilled in the art that many modifications, both to materials and
methods, may be practiced without departing from the purpose and
interest of this invention.
6. EXAMPLES
6.1 Materials and Procedures
[0227] Reagents and solvents used below can be obtained from
commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis.,
USA). Routine chemical analyses were conducted using NMR, MS and
HPLC. Significant NMR peaks are tabulated by chemical shift and
labeled with multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br s, broad singlet) and number of protons.
Mass spectrometry data is provided in relation to the mass of the
parent ion, M. HPLC data is provided as a purity percentage.
[0228] X-ray powder diffraction (XRPD) data were obtained by one of
the two following methods. In certain experiments, XRPD analyses
were performed using an Inel XRG-3000 diffractometer equipped with
a CPS (Curved Position Sensitive) detector with a 2.theta. range of
120.degree.. Real time data were collected using Cu-K.alpha.
radiation starting at approximately 2.5.degree. 2.theta. at a
resolution of 0.03.degree. 2.theta.. The tube voltage and amperage
were set to 40 kV and 30 mA, respectively. The slit was set at 5 mm
by 130 or 160 .mu.m. Samples were prepared for analysis by packing
them into thin-walled glass capillaries. Each capillary was mounted
onto a goniometer head that is motorized to permit spinning of the
capillary during data acquisition. The samples were analyzed for
five or ten minutes. Instrument calibration was performed using a
silicon reference standard.
[0229] In other experiments, XRPD analyses were performed using a
Shimadzu XRD-6000 X-ray powder diffractometer using Cu-K.alpha.
radiation. The instrument is equipped with a long fine focus X-ray
tube. The tube voltage and amperage were set to 40 kV and 40 mA,
respectively. The divergence and scattering slits were set at
1.degree. and the receiving slit was set at 0.15 mm. Diffracted
radiation was detected by a NaI scintillation detector. A 9-20
continuous scan at 3.degree./min (0.4 sec/0.02.degree. step) from
2.5 to 40.degree. 2.theta. was used. A silicon standard was
analyzed to check the instrument alignment. Data were collected and
analyzed using XRD-6000 v. 4.1. Samples were prepared for analysis
by placing them in a silicon sample holder.
[0230] In particular embodiments, the experimental error associated
with a measured XRPD peak position is about .+-.0.1.degree.
2.theta..
[0231] DSC was performed using a TA Instruments 2920 differential
scanning calorimeter. The sample was placed into an aluminum DSC
pan, and the weight accurately recorded. The pan was covered with a
lid and then crimped, unless otherwise noted. The sample cell was
equilibrated at 25.degree. C. and heated under a nitrogen purge at
a rate of 10.degree. C./min, up to a final temperature of
350.degree. C. Indium metal was used as the calibration
standard.
[0232] Modulated DSC (MDSC) data were obtained on a TA Instruments
2920 differential scanning calorimeter equipped with a refrigerated
cooling system (RCS). The sample was placed into an aluminum DSC
pan, and the weight accurately recorded. The pan was covered with a
lid and then crimped. MDSC data were obtained using a modulation
amplitude of +/-0.80.degree. C. and a 60 second period with an
underlying heating rate of 2.degree. C./min from -20 to 120.degree.
C. The temperature and the heat capacity were calibrated using
indium metal and sapphire as the calibration standards,
respectively. The reported glass transition temperature was
obtained from the half-height/inflection of the step change in the
reversible heat flow versus temperature curve.
[0233] TGA analyses were performed using a TA Instruments 2950
thermogravimetric analyzer. Each sample was placed in an aluminum
sample pan and inserted into the TGA furnace. Conditions of routine
thermal gravimetric analysis involved equilibrating the furnace at
25.degree. C., followed by heating under nitrogen at a rate of
10.degree. C./min up to a final temperature of 350.degree. C.
Modifications were made to this procedure in cases involving
non-routine analysis, such as not equilibrating prior to heating,
heating at different rates and heating to temperatures below
350.degree. C. Nickel and Alumel.TM. were used as calibration
standards.
[0234] Hot stage microscopy was performed using a Linkam hot stage
(model FTIR 600) mounted on a Leica DM LP microscope. Samples were
observed using a 20.times. objective and a lambda plate with
crossed polarizers. Samples were placed on a coverslip, and another
coverslip was then placed over the sample. Each sample was visually
observed as the stage was heated. Images were captured using a SPOT
Insight.TM. color digital camera with SPOT Software v. 3.5.8. The
hot stage was calibrated using USP melting point standards.
[0235] TG-IR analyses were acquired on a TA Instruments 2050 TGA
analyzer interfaced to a Magna 560.RTM. FT-IR spectrophotometer
(Thermo Nicolet) equipped with an Ever-Glo mid/far IR source, a
potassium bromide (KBr) beamsplitter, and a deuterated triglycine
sulfate (DTGS) detector. The TGA instrument was operated under a
flow of helium at 90 and 10 cc/min for the purge and balance,
respectively. Each sample was placed in a platinum sample pan,
inserted into the TGA furnace, accurately weighed by the
instrument, and the furnace was heated from 20.degree. C. to 200 or
250.degree. C. at a rate of 20.degree. C./min. The TGA instrument
was started first, immediately followed by the FT-IR instrument.
Each IR spectrum represents 32 co-added scans collected at a
spectral resolution of 4 cm.sup.-1. A background scan was collected
before beginning the experiment. Wavelength calibration was
performed using polystyrene. The TGA calibration standards were
nickel and Alumel.TM.. Volatiles were identified from a search of
the High Resolution Nicolet TGA Vapor Phase spectral library.
[0236] Moisture sorption/desorption data were collected on a VTI
SGA-100 Vapor Sorption Analyzer. Sorption and desorption data were
collected over a range of 5% to 95% relative humidity (RH) at 10%
RH intervals under a nitrogen purge. For some samples, a step at
90% RH was added to the sorption cycle. Samples were not dried
prior to analysis. Equilibrium criteria used for analysis were less
than 0.0100% weight change in 5 minutes, with a maximum
equilibration time of 3 hours if the weight criterion was not met.
Data were not corrected for the initial moisture content of the
samples. NaCl and PVP were used as calibration standards.
[0237] The IR spectra were acquired on a Magna-IR 860.RTM. FT-IR
spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo
mid/far IR source, an extended range potassium bromide (KBr)
beamsplitter, and a deuterated triglycine sulfate (DTGS) detector.
An attenuated total reflectance (ATR) accessory (the
Thunderdome.TM., ThermoSpectra-Tech), with a germanium (Ge) crystal
was used for data acquisition. Each spectrum represents 256
co-added scans collected at a spectral resolution of 4 cm.sup.-1. A
background data set was acquired with air. A Log 1/R
(R=reflectance) spectrum was acquired by taking a ratio of these
two data sets against each other. Wavelength calibration was
performed using polystyrene.
[0238] In certain experiments, FT-Raman spectra were acquired on a
Raman accessory module interfaced to a Magna 860.RTM. FT-IR
spectrophotometer (Thermo Nicolet). This module used an excitation
wavelength of 1064 nm and an indium gallium arsenide (InGaAs)
detector. Approximately 0.7 W of Nd:YVO.sub.4 laser power was used
to irradiate the sample. The samples were prepared for analysis by
placing the material in a glass tube or capillary, which was then
positioned in a gold-coated tube or capillary holder in the
accessory. A total of 256 sample scans were collected at a spectral
resolution of 4 cm.sup.-1, using Happ-Genzel apodization.
Wavelength calibration was performed using sulfur and
cyclohexane.
[0239] In other experiments, FT-Raman spectra were acquired on an
FT-Raman 960 spectrometer (Thermo Nicolet). This module used an
excitation wavelength of 1064 nm and an indium gallium arsenide
(InGaAs) detector. Approximately 1 W of Nd:YVO.sub.4 laser power
was used to irradiate the sample. The samples were prepared for
analysis by placing the material in a glass tube or capillary,
which was then positioned in a gold-coated tube or capillary holder
in the accessory. A total of 256 sample scans were collected at a
spectral resolution of 4 cm.sup.-1, using Happ-Genzel apodization.
Wavelength calibration was performed using sulfur and
cyclohexane.
[0240] Coulometric Karl Fisher (KF) analysis for water
determination was performed using a Mettler Toledo DL39 Karl
Fischer titrator. Approximately 14-32 mg of sample was placed in
the KF titration vessel containing Hydranal-Coulomat AD and mixed
for 60 seconds to ensure dissolution. The sample was then titrated
by means of a generator electrode which produces iodine by
electrochemical oxidation: 2.GAMMA.=>I.sub.2+2e. Three
replicates were obtained to ensure reproducibility.
6.2 Example 1
Synthesis
[0241] Three different synthetic methods were used to obtain the
compounds of this invention. A first method comprises the isolation
of (-)-venlafaxine, followed by selective demethylation. A second
method comprises separating a racemic mixture of
(.+-.)-O-desmethylvenlafaxine into its optically pure components. A
third method comprises synthesizing
(.+-.)-O-benzyl-O-desmethylvenlafaxine, separating the resulting
optically pure components, and debenzylating said components.
6.2.1 Synthesis and Resolution of Venlafaxine
6.2.1.1 1-[Cyano-(4-methoxyphenyl)methyl]cyclohexanol
[0242] A solution of 4-methoxybenzylnitrile (53.5 g, 0.36 mol) in
400 mL THF was cooled to -78.degree. C. followed by slow addition
of a 2.0 M THF solution of lithium diisopropylamide (200 mL, 0.40
mol) maintaining the reaction temperature below -65.degree. C. The
reaction was stirred at -78.degree. C. for 30 minutes.
Cyclohexanone (39.5 g, 0.40 mol) was added at a rate such that the
reaction temperature did not rise above -65.degree. C. After the
addition reaction was stirred at -78.degree. C. for 2 hours, it was
poured into 1 L saturated aqueous NH.sub.4Cl containing ice. The
mixture was stirred for 15 minutes and was extracted with ethyl
acetate (4.times.200 mL). Combined ethyl acetate layer was washed
with water (3.times.100 mL), brine (1.times.100 mL) and dried
(Na.sub.2SO.sub.4). Ethyl acetate was evaporated in vacuo to give
colorless solid that was trichurated with hexane. The precipitate
was filtered, washed with hexane, and dried in vacuo to give a
colorless solid (72.0 g, 80.7% yield). .sup.1H (CDCl.sub.3); 7.30
and 6.90 (q, 4H), 3.80 (s, 3H), 3.75 (s, 1H), 1.55 (m, 10H);
.sup.13C (CDCl.sub.3): 159.8, 130.8, 123.8, 120.0, 114.1, 72.9,
55.5, 49.5, 34.9, 25.3, 21.6.
6.2.1.2 1-[2-Amino-1-(4-methoxyphenyl)ethyl]cyclohexanol
[0243] A 3 L, three-neck flask equipped with a mechanical stirrer
and a thermocouple was charged with
1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (40.0 g, 0.16 mol) and
1 L methanol. To the resulting stirred solution was added cobalt
chloride (42.4 g, 0.32 mol) and the reaction was stirred until a
clear dark blue solution was obtained. Sodium borohydride (62.0 g,
1.63 mol) was added in small lots maintaining the reaction
temperature below 35.degree. C. A dark black precipitate was formed
along with vigorous evolution of gas as soon as sodium borohydride
was added. After completion of addition the slurry was stirred at
room temperature for 2 hours. TLC examination indicated complete
disappearance of the starting material. The reaction was cooled in
ice/water and 1 L of 3N HCl was added slowly. Reaction temperature
was maintained below 25.degree. C. Reaction was stirred for 30
minutes after completion of the addition. Small amount of black
precipitate was still observed. Methanol was removed in vacuo
followed by extraction of the aqueous layer with ethyl acetate
(3.times.300 mL). The aqueous layer was cooled in ice/water and was
basified (pH paper) by slow addition of concentrated NH.sub.4OH
(ca. 600 mL). Reaction temperature was maintained below 25.degree.
C. Reaction was extracted with ethyl acetate (4.times.200 mL).
Combined ethyl acetate layer was washed with water (3.times.100
mL), brine (1.times.100 mL), and dried (Na.sub.2SO.sub.4). Ethyl
acetate was evaporated in vacuo to give yellow gum (34.0 g, 83.6%
yield). .sup.1H (CDCl.sub.3): 7.20 and 6.85 (q, 4H), 3.80 (s, 3H),
3.20 (m, 2H), 2.70 (t, 3H), 2.35 (br s, 3H), 1.40 (m, 10H);
.sup.13C (CDCl.sub.3): 158.4, 132.6, 130.6, 113.7, 73.7, 56.7,
55.3, 42.4, 37.3, 34.5, 26.0, 21.9.
6.2.1.3 (.+-.)-Venlafaxine
[0244] 1-[2-Amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (33.0 g,
0.13 mol) was dissolved in 88% formic acid (66.0 g, 55 mL, 1.43
mol) and water (330 mL) followed by addition of 37% aqueous
formaldehyde (44.4 g, 41 mL, 1.48 mol). The resulting solution was
refluxed for 20 hours, cooled to room temperature and was
concentrated to 150 mL, adjusted to pH 2.0 with 3N HCl, and
extracted with ethyl acetate (ca. 6.times.50 mL) until pink
impurity was removed. The aqueous layer was cooled in ice/water and
was basified by slow addition of 50% NaOH. The aqueous layer was
extracted with ethyl acetate (3.times.75 mL). Combined ethyl
acetate layer was washed with water (3.times.25 mL), brine (1
.times.25 mL) and dried (Na.sub.2SO.sub.4). Ethyl acetate was
evaporated in vacuo to give yellow gum that turned slowly in to
pale yellow solid (34.0 g, 92.6% yield). .sup.1H (CDCl.sub.3): 7.05
and 6.80 (q, 4H), 3.80 (s, 3H), 3.30 (t, 1H), 2.95 (dd, 1H), 2.35
(s, 6H), 2.30 (dd, 1H), 1.30 (m, 10H); .sup.13C (CDCl.sub.3):
158.4, 132.9, 130.3, 113.5, 74.4, 61.4, 55.3, 51.8, 45.6,
38.2,31.3,26.2, 21.8, 21.5. MS (277, M+).
6.2.1.4 Tartrate Salts of Venlafaxine
[0245] Venlafaxine hydrochloride was prepared from venlafaxine
freebase by the addition of hydrochloric acid in an appropriate
solvent or according to U.S. Pat. No. 4,535,186.
[0246] A mixture of 2.50 kg of
1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl) cyclohexanol
hydrochloride, 16.8 kg of ethyl acetate and 14.0 kg of 1 N NaOH
(aq) was stirred for 15 min. The stirring was stopped and the lower
layer removed. The organic layer was washed twice with 3.5 kg of
water. 2.4 kg of methanol and 1.78 kg of di-p-toluoyl-D-tartaric
acid in 7.9 kg ethyl acetate was added. The mixture was stirred at
reflux (.about.65.degree. C.) for 15 min and cooled to 55.degree.
C. The solution was seeded with 43 g of
(R)-1-(2-(dimethylamino)-1-(4-methoxyphenyl)
ethyl)cyclohexanol-hemi-D-di-p-toluoyltartaric acid salt in 0.750
kg of ethyl acetate. The slurry was aged at 55.degree. C. for 15
minutes, cooled to 30.degree. C. over 110 minutes. The mixture was
then cooled to 0.degree. C. over 1 hour and filtered. The cake was
washed twice with a mixture of 0.23 kg of methanol and 2.3 kg ethyl
acetate and dried in vacuo at 40-50.degree. C. to yield 1.53 kg of
(R)-1-(2-(dimethylamino)-1-(4-methoxyphenyl)
ethyl)cyclohexanol-hemi-D-di-p-toluoyltartaric acid salt (99.1%
ee). .sup.1H NMR (DMSO-D.sub.6): 0.80-1.6 (m, 10H), 2.35 (s, 9H),
2.86 (m, 1H), 2.98 (m, 1H), 3.33 (m, 1H), 3.72 (s, 3H), 5.62 (s,
2H), 6.81 (d, 2H, J=8.5 Hz), 7.12 (d, 2H, J=8.5 Hz), 7.31 (d, 4H,
J=8.3 Hz), 7.85 (d, 4H, J=8.3 Hz).
6.2.1.5 (-)-Venlafaxine
[0247] 50 mL cold 2N NaOH was added to
(R)-(-)-venlafaxine.di-p-toluoyl-D-tartrate salt (5.3 g, 8.0 mmol)
and the aqueous layer was extracted with ethyl acetate (3.times.100
mL). Combined ethyl acetate layer was washed with cold 2N NaOH (1
.times.25 mL) and water until aqueous wash was neutral. Ethyl
acetate layer was dried (Na.sub.2SO.sub.4), ethyl acetate
evaporated to give (-)-venlafaxine as colorless solid (2.2 g,
quantitative yield), e.e. (HPLC): >99.95. .sup.1H, .sup.13C and
MS data as in (.+-.)-venlafaxine.
6.2.2 Synthesis and Resolution of (-)-O-desmethylvenlafaxine
6.2.2.1 (.+-.)-O-desmethylvenlafaxine
[0248] A solution of diphenylphosphine (3.0 g, 16.1 mmol) in 20 mL
THF was cooled to -10.degree. C. followed by slow addition of a 1.6
M THF solution of n-BuLi (12.7 mL, 20.2 mmol) at a rate such that
reaction temperature did not rise above 0.degree. C. The reaction
was stirred at 0.degree. C. for 30 minutes. A solution of
(.+-.)-venlafaxine (1.0 g, 3.6 mmol) in 10 mL THF was added slowly
at 0.degree. C. The reaction was stirred at 0.degree. C. for 15
minutes and allowed to warm to room temperature and stirred for 1
hour. It was then refluxed overnight. The reaction was cooled to
room temperature and was poured slowly into 30 mL cold 3N HCl
maintaining the temperature below 15.degree. C. After stirring for
10 minutes, the aqueous layer was extracted with ethyl acetate
(3.times.30 mL). The aqueous layer was adjusted to pH 6.8-6.9 by
slow addition of solid NaHCO.sub.3. It was then saturated by adding
NaCl and was extracted with ethyl acetate (6.times.30 mL). Combined
ethyl acetate layer was dried (Na.sub.2SO.sub.4), ethyl acetate was
evaporated in vacuo to give colorless solid. The solid was
triturated with cold ethyl acetate, filtered, washed with cold
ethyl acetate to give colorless solid (0.700 g, 73.8% yield).
.sup.1H (DMSO, d.sub.6): 9.30 (br s, 1H); 7.10 and 6.80 (q, 4H),
5.60 (br s, 1H), 3.15 (dd, 1H), 2.88 (t, 1H), 2.50 (dd, 1H), 2.30
(s, 6H), 1.35 (m, 10H); .sup.13C (DMSO, d.sub.5): 155.5, 131.7,
130.1, 114.4, 72.6, 60.4, 51.6, 45.3, 37.2, 32.4, 25.7, 21.2. MS:
(264, M+1).
6.2.2.2 (-)-O-desmethylvenlafaxine
[0249] (-)-O-desmethylvenlafaxine was prepared from (-)-venlafaxine
by following the procedure described above.
(-)-O-desmethylvenlafaxine: colorless solid, [.alpha.].sub.D=-35.2
(c=0.25, EtOH), % purity (HPLC): >99% e.e. (HPLC): >99%.
.sup.1H, .sup.13C and MS data as in
(.+-.)-O-demethylvenlafaxine.
6.2.2.3 (-)-O-desmethylvenlafaxine Directly from Venlafaxine
DTTA
[0250] (-)-O-desmethylvenlafaxine can also be directly prepared
from (-)-venlafaxine-hemi-DTTA salt by following the procedure
described below.
6.2.2.4 (-)-Venlafaxine
[0251] A mixture of 1.95 kg of
(R)-1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)
cyclohexanol-hemi-D-di-p-toluoyltartaric acid salt, 12.03 kg of
MTBE and 5.85 kg of 1M NaOH (aq) was stirred for 15 min. The
stirring was stopped and the lower layer removed. The organic layer
was washed twice with 5.46 kg of water. The organic layer was
concentrated to 5 L. 3.90 kg of anhydrous tetrahydrofuran was added
and the mixture was distilled to a volume of 4.5 L to yield
(-)-venlafaxine as a solution in THF.
[0252] A solution of lithium diphenylphosphide was generated by
adding 6.2 kg of n-butyllithium, 1.6M (15%wt) to a mixture of 22.9
kg of tetrahydrofuran and 2.2 kg of diphenylphosphine. The THF
solution of (-)-venlafaxine was added to the lithium
diphenylphosphide. The mixture was stirred at 50.degree. C. and
hold until reaction is complete (approximately 24 hr). The mixture
was cooled to 22.degree. C., 11.95 kg of DI water and 3.94 kg of 6N
HCl was added. The mixture was stirred for 15 minutes, the stirring
stopped and the upper organic phase was removed and discarded. The
aqueous layer was washed twice with 7.98 kg of methylene chloride.
The pH of the aqueous was adjusted to 9.5 using concentrated
ammonium hydroxide. And 19.4 kg of 2-methyltetrahydrofuran was
added. The mixture was heated to 65.degree. C. and the aqueous
phase was removed. The organic was washed at 65.degree. C. with 8
kg of water and the organic was concentrated to 4.5 L. 14.3 kg of
ethyl acetate was added and the mixture stirred at 45-55.degree. C.
for 30 minutes. The mixture was stirred at 0.degree. C. for 30 min.
The slurry was filtered and the cake was washed twice with 2.8 kg
of ethyl acetate. The solid was dried under vacuum (>28in Hg) at
40-50.degree. C. to yield 0.903 kg of
(R)--O-desmethyl-1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexan-
ol (99.3% ee). .sup.1H NMR (DMSO-d.sub.6): 0.80-1.8 (m, 10H), 2.15
(s, 6H), 2.37 (dd, 1H, J=12.5, 6.5), 2.73 (dd, 1H, J=8.5, 6.5 Hz),
2.99 (dd, 1H, J=12.5, 8.5), 5.42 (br.s 1H), 6.65 (d, 2H, J=8.5 Hz),
6.97 (d, 2H, J=8.5 Hz), 9.16 (br. s, 1H).
6.2.2.5 (-)-O-desmethylvenlafaxine Hydrochloride Salt
[0253] 80.4 g of
(R)--O-desmethyl-1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)
cyclohexanol was charged to a 1 L round bottomed flask fitted with
an overhead mechanical stirrer. 326.0 g of methanol and 80.3 g of a
15% w/w aqueous solution of hydrochloric acid was added. The
solution was stirred at 20.degree. C. for 15 minutes and added to
1,797 g of heated (40.degree. C.) methyl tert-butyl ether (MTBE).
The mixture was stirred at 40.degree. C. for 20 minutes and cooled
to 20 .degree. C. The mixture was stirred at 20.degree. C. for one
hour and seeded with 1.6 g of
(R)--O-desmethyl-1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexan-
ol hydrochloride monohydrate seeds as a slurry in 21 mL of MTBE.
The contents of the 5 L flask were mixed at 20.degree. C. for 2
hours to form a slurry. 1.6 L of MTBE was added to the 5 L flask
and stirred at 20.degree. C. for 2 hours. The mixture was filtered
on a medium fritted funnel to isolate the product and the cake was
washed twice (2.times.241.0 g) with MTBE. The filter cake was
pulled dry under vacuum on the medium fritted funnel for 1 hour to
yield 86.3 g of (R)--O-desmethyl
1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)cyclohexanol
hydrochloride monohydrate. .sup.1H NMR (DMSO-d.sub.6): 0.80-1.70
(10H, m), 2.60 (3H, s), 2.64 (3H, s), 3.00 (1H, dd, J=9.3, 3.7 Hz),
3.46 (1H, br.t), 3.63 (1H, br.d), 4.52 (1H, s), 6.75 (2H, d, J=8.3
Hz), 7.11 (2H, d, J=8.3 Hz), 9.43 (1H, br.s), 9.50 (1H, s).
6.2.3 Resolution of (-)-O-desmethylvenlafaxine
[0254] (-)-O-desmethylvenlafaxine was synthesized via the
resolution of (.+-.)-O-desmethylvenlafaxine.
[0255] 1.0 g of (.+-.)-O-desmethylvenlafaxine, 0.89 g (24 mmol) of
(R)-1-phenyl-1-cyclohexyl-1-hydroxyacetic acid, 7.9 g of ethanol
and 1.05 g of water were charged to a 25 mL flask. The mixture was
stirred at 75.degree. C. for 30 min and cooled to room temperature.
The resulting solid was collected by filtration and washed with
ethanol. The solid was dried to give 790 mg of
(R)-1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol
(R)-1-phenyl-1-cyclohexyl-1-hydroxyacetic aci salt (99.42% ee).
.sup.1H NMR (CDCl.sub.3): 4.
6.2.3.1 (-)-O-desmethylvenlafaxine Hydrochloride Salt
[0256]
(R)-1-(2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol
(R)-1-phenyl-1-cyclohexyl-1-hydroxyacetic acid salt (2.0 g, 4 mmol)
was dissolved into methanol (5.4 mL) and 15% (w/w) HCl in water
(1.05 g). The methanol/hydrochloric acid solution was added with
stirring to methyl-tert butyl ether (MTBE) (32 mL) at 35-40.degree.
C. Following the addition of the methanol/hydrochloric acid
solution the mixture was stirred at 35-40.degree. C. for 60 min and
cooled to room temperature. The mixture was seeded with
(-)-O-desmethylvenlafaxine monohydrate and stirred at 20.degree. C.
for 3 hours. The solid was collected by filtration and-washed with
MTBE (20 mL). The solid was dried to give 730 mg of
1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl) cyclohexanol
hydrochloride. The solid was analyzed (5.49% water, impurities
<0.05%, DSC 101.38), .sup.1H NMR (DMSO-d.sub.6): 0.80-1.70 (10H,
m), 2.60 (3H, s), 2.64 (3H, s), 3.00 (1H, dd, J=9.3, 3.7 Hz), 3.46
(1H, br.t), 3.63 (1H, br.d), 4.52 (1H, s), 6.75 (2H, d, J=8.3 Hz),
7.11 ( 2H, d, J=8.3 Hz), 9.43 (1H, br.s), 9.50 (1H, s).
[0257] (R)-1-Phenyl-1-cyclohexyl-1-hydroxyacetic acid is made
according to the procedure outlined in Tetrahedron: Asymmetry 14
(2003) 3593, which is hereby incorporated by reference.
6.2.4 Synthesis and Resolution of
O-benzyl-O-desmethylvenlafaxine
[0258] (-)-O-Desmethylvenlafaxine was prepared by synthesizing and
resolving (.+-.)-O-desmethylvenlafaxine.
6.2.4.1 (.+-.)-O-Benzyl-O-desmethylvenlafaxine
[0259] In certain embodiments, the following procedure was
employed. 150 g of 2-(4-benzyloxy)phenyl-N,N-dimethylacetamide, 945
g (1062 mL) of THF was charged to a 5 L jacketed reactor. 550 mL of
isopropylmagnesium chloride (2.0 M in tetrahydrofuran) was added
and the mixture was stirred for 1 h. 115 g of cyclohexanone was
added to the reactor and mixed for 1 h. 360 g of RedAl (sodium
bis(2-methoxyethoxy)aluminum hydride-65% w/w in toluene) was added
to the reactor and stirred for 16 h. When the reaction was complete
the mixture was added to 2005 g of 22% w/w aqueous citric acid. 420
g (600 mL) of heptane was charged to the reactor and stirred for 15
min. The stirring was stopped and the top layer was removed. 250 g
of 50% NaOH was added to adjust the pH to 9-10, followed by
stirring-1114 g (1500 mL) of MTBE was added to the reactor. The
mixture was warmed to 45.+-.5.degree. C. to dissolve the solids.
The stirring was stopped and the bottom layer was removed. The
organic layer was washed twice with 750 g of water at 45.degree. C.
750 mL of MTBE was removed by distillation and 750 mL of methanol
was added. About 750 mL of MTBE/methanol was removed by
distillation and 300 g of methanol and 300 g of water were added.
The slurry was cooled to 0.degree. C. and stirred for 30 min. The
slurry was filtered and the solid washed with 375 g of (4:1
methanol:water). The solid was dried to yield 161 g of
1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl) cyclohexanol.
[0260] In certain embodiments, the following procedure was
employed. To a 200 gallon reactor was charged 22.98 kg of
2-(4-benzyloxy)phenyl-N,N-acetamide and 145.1 kg of THF. With
agitation, the temperature was adjusted to 5.degree. C. to
10.degree. C. To the reactor was charged 82.9 kg of
isopropylmagnesium chloride, 2.0M in THF, while maintaining the
temperature between 5.degree. C. to 35.degree. C. The lines were
rinsed with 2.78 kg of THF. The contents were agitated for 61
minutes at 10.degree. C. to 20.degree. C. To the reactor was added
9.31 kg of cyclohexanone while maintaining the temperature between
5.degree. C. to 35.degree. C. The lines were rinsed with 2.77 kg of
THF. The temperature was adjusted to 15.degree. C. to 25.degree. C.
and the contents were agitated for 17 minutes at this temperature
range after which the reaction was complete. To the reactor was
charged 55.8 kg of sodium bis(2-methoxyethoxy)aluminum hydride (65
wt % in toluene) while maintaining the temperature at 15.degree. C.
to 35.degree. C. The contents were agitated for 10 h (<3%
starting material remained). The reaction mixture was added to
334.1 kg of 22% citric acid solution cooled to 0.degree. C. to
2.degree. C. THF (22.9 kg) and n-heptane (63.3 kg) were added to
the reaction. The mixture was agitated for 15 minutes then the
stirring was stopped and the phases were allowed to separate. The
top layer was removed and the reactor was charged with 45.4 kg of
50% sodium hydroxide. The reactor was charged 169.9 kg of MTBE and
the temperature was adjusted to 40-50.degree. C. The contents were
agitated for 14 minutes and the agitation was stopped to allow the
phases to separate for 15 minutes. The aqueous layer was removed
and 115 L of USP purified water was added. The temperature was
adjusted to 40.degree. C. to 50.degree. C. The contents were
agitated for 15 minutes and the agitation was stopped to allow the
phases to separate for 13 minutes. The aqueous bottom layer was
removed. The reactor was charged with 115 L of USP purified water
and the temperature was adjusted to 40.degree. C. to 50.degree. C.
The contents were agitated for 15 minutes and the agitation was
stopped to allow the phases to separate. The aqueous bottom layer
was removed. The solution was distilled under vacuum to a final
volume of 188 L. To the reactor was charged 115.2 kg of methanol
and the solution was distilled under vacuum to a final volume of
131 L. To the reactor was charged 46.0 kg of methanol and 57 L of
USP purified water. The temperature was adjusted to 0.degree. C.
The slurry was stirred for 41 minutes at -5.degree. C. to 5.degree.
C. and the mixture was filtered. The cake was washed with 46.2 kg
of methanol and 11.6 kg of USP purified water (cooled to -5.degree.
C. to 5.degree. C.). The wet cake (30.66 kg) was dried at
40-50.degree. C. to yield 24.47 kg of
1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl)cyclohexanol.
6.2.4.2 (-)-O-Benzyl-O-desmethylvenlafaxine-hemi-D-DTTA Salt
[0261] In certain embodiments, the following procedure was
employed. 160 g of
1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl)cyclohexanol, 100 g
of D-di-p-toluoyltartaric acid, 1.6 L of acetone, 150 g of water
were added to a 5 L reactor and heated to 50.degree. C. The mixture
was stirred at 50.degree. C. for 15 minutes and cooled to 0.degree.
C. The mixture was stirred at 0.degree. C. for 120 minutes and
filtered. The cake was washed with 600 mL of acetone and dried in
vacuo at 40-50.degree. C. to yield 114.3 g of
(R)-1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl)cyclohexanol-di-p-tol-
uoyl-D-tartaric acid salt.
[0262] In certain embodiments, the following procedure was
employed. To a reactor was charged 60.64 kg of
1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl) cyclohexanol,
42.01 kg of D-di-p-toluoyltartaric acid, 512.7 kg of acetone, and
61 L of USP purified water. The temperature was adjusted to
50.degree. C. to 55.degree. C., and the contents were agitated at
this temperature range for 16 minutes. The mixture was cooled to
36.degree. C. and stirred at 36.degree. C. for a period of 35
minutes. The mixture was cooled to -2.degree. C. to 2.degree. C.
over 105 minutes and agitated for 122 minutes. The mixture was
filtered and the cake was washed twice with acetone (122.0 kg and
121.8 kg), cooled to -5.degree. C. to 5.degree. C. The wet cake
(47.06 kg) was dried at 40-50.degree. C. to yield 41.50 kg of
(R)-1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl) cyclohexanol
di-p-toluoyl-D-tartaric acid salt.
6.2.4.3 (-)-O-Benzyl-O-desmethylvenlafaxine
[0263] In certain embodiments, the following procedure was
employed. A 5 L flask was charged with 190 g of
(R)-1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl)cyclohexanol-D-di-p-t-
oluoyltartaric acid salt, 703 g of MTBE and 870 g of 1 N NaOH. The
mixture was stirred at 45.degree. C., the aqueous was removed and
the organic layer was washed with water (475 g.times.2). The MTBE
layer was distilled to 450 mL, 703 g of methanol was added and the
mixture was distilled to 450 mL. The slurry was diluted with 450 g
of water and the mixture cooled to 0.degree. C. The mixture was
filtered and washed with 435 mL of methanol/water to yield after
drying 112 g of
(R)-1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl)cyclohexanol.
.sup.1H NMR (DMSO-d.sub.6): 0.8-1.6 (10H, m), 2.12 (6H, s), 2.41
(1H, dd, J=6.9, 12.3 Hz), 2.77 (1H, t, J=6.9 Hz), 2.94 (1H, dd,
J=7.9, 12.3 Hz), 5.05 (2H, s), 5.23 (1H, s), 6.89 (2H, d, J=8.7
Hz), 7.11 (2H, d, J=8.7 Hz), 7.3-7.5 (5H, m).
[0264] In certain embodiments, the following procedure was
employed. A reactor was charged 69.49 kg of
(R)-1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl) cyclohexanol
di-p-toluoyl-D-tartaric acid salt, 265.7 kg of MTBE, and 328.9 kg
of 1N NaOH. The temperature was adjusted to 48-52.degree. C. and
the contents were agitated for 17 minutes. The agitation was
stopped and the phases were allowed to separate for a period of 8
minutes. The aqueous bottom phase was removed, 180.1 kg of USP
purified water was added and the temperature was adjusted to
48.degree. C. to 52.degree. C. The mixture was agitated at
48.degree. C. to 52.degree. C. for 25 minutes, the agitation was
stopped and the phases were allowed to separate for a period of 7
minutes. The aqueous bottom phase was removed and 179.8 kg of USP
purified water was added. The mixture was agitated at 48.degree. C.
to 52.degree. C. for 17 minutes, the agitation was stopped and the
phases were allowed to separate for a period of 7 minutes. The
aqueous bottom layer was removed and the solution was distilled to
a final volume of 170 L. 265.7 kg of methanol was added and the
solution was distilled to a final volume of 170 L. The reaction was
cooled to 23.degree. C. to 27.degree. C. over 1 hour and 9 minutes.
To the reactor was charged 170 L of USP purified water while
maintaining the temperature at 23.degree. C. to 33.degree. C.
during the addition. The slurry was cooled to -5.degree. C. to
5.degree. C. over 1 hour and 17 minutes and was agitated at
-5.degree. C. to 5.degree. C. for 34 minutes. The mixture was
filtered and the cake was washed with 64.7 kg of methanol and 82 L
of USP purified water (cooled to -5.degree. C. to 5.degree. C.).
The wet cake (46.61 kg) was dried at 40-50.degree. C. to yield
42.47 kg of (R)-1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl)
cyclohexanol.
6.2.4.4 (-)-O-desmethylvenlafaxine Hydrochloride Salt
[0265] In certain embodiments, the following procedure was
employed. 19.5 g of
(R)-1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl) cyclohexanol,
400 mg of 10% palladium on carbon, 58 mL of methanol, 4.5 mL of 37
wt % aqueous hydrochloric acid and 6.8 g of water were charged to a
hydrogenation vessel. The mixture was reacted with 50 psi of
hydrogen for 3 days. The resulting mixture was filtered and the
catalyst was washed with 14 mL of methanol. The combined filtrate
and mother liquor was added to 434 mL of MTBE at 40.degree. C. The
mixture was cooled to 20.degree. C. and seeded with
(-)-O-desmethylvenlafaxine hydrochloride monohydrate. The mixture
was stirred for 1 h at 20.degree. C. and 290 mL of MTBE was added.
The mixture was stirred for 2 h, filtered and washed with MTBE
(2.times.70 mL) to yield after drying 14.4 g of
1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol
hydrochloride monohydrate. .sup.1H NMR (DMSO-d.sub.6): 0.80-1.70
(10H, m), 2.60 (3H, s), 2.64 (3H, s), 3.00 (1H, dd, J=9.3, 3.7 Hz),
3.46 (1H, br.t), 3.63 (1H, br.d), 4.52 (1H, s), 6.75 (2H, d, J=8.3
Hz), 7.11 (2H, d, J=8.3 Hz), 9.43 (1H, br.s), 9.50 (1H, s).
Solid-state analysis confirmed that this material was the Form A
crystal form.
[0266] In certain embodiments, the following procedure was
employed. 1.0 kg of
(R)-1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl)cyclohexanol,
20 g of 10% palladium on carbon, 1.76 kg of ethanol and 550 g of 20
wt % hydrochloric acid were charged to a hydrogenation vessel. The
mixture was reacted with hydrogen until all the starting material
had been consumed. The resulting mixture was filtered and the
catalyst was washed with 380 g of ethanol. The combined filtrate
and mother liquor was added to 4.96 kg of MTBE at 40.degree. C. The
mixture was cooled to 20.degree. C. and seeded with 20 g of
1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl) cyclohexanol
hydrochloride monohydrate. The mixture was stirred for 2 h at
40.degree. C. and 6.06 kg of MtBE was added over 8 hours. The
mixture was stirred for 2 h and cooled to 0.degree. C. The slurry
was filtered, washed with 1.67 kg of MTBE:ethanol (5.4:1) and 1.66
kg of MTBE to yield after drying 1.1 kg of
1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl) cyclohexanol
hydrochloride monohydrate. The resulting product was confirmed to
be form A.
[0267] In certain embodiments, the following procedure was
employed. The reactor was charged with 31.80 kg of
(R)-1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl) cyclohexanol.
A slurry of 0.636 kg of palladium on carbon in 3.96 kg of ethanol
(5% denatured with methanol). The atmosphere of the reactor was
evacuated and replaced with nitrogen three times to exclude air.
The reactor was charged with 56.1 kg of ethanol followed by 17.4 kg
of 20 wt % HCl solution. The temperature was adjusted to
20-25.degree. C. The solids completely dissolved after 35 minutes
while bubbling nitrogen through the solution to degas. The reaction
was pressurized once with 45 to 55 psig of hydrogen, vented, and
then repressurized to 45 to 55 psig with hydrogen. The mixture was
agitated at 20 to 30.degree. C. until the reaction was complete.
The hydrogen was vented and the reactor was pressurized with
nitrogen to 50 to 60 psig three times. The reaction mixture was
filtered through a 3 .mu.m filter and the reactor/filter was rinsed
with 12.0 kg of ethanol. The combined filtrate/washes were added to
157.0 kg of MTBE at 40.degree. C. to 45.degree. C. Seeds of the
hydrochloride salt of (-)-O-desmethylvenlafaxine (635g) were added
and the mixture was mixed for 2 hours and 4 minutes at 35.degree.
C. to 45.degree. C. 191.9 kg of MTBE was added over a period of 8
hours while maintaining the temperature at 35.degree. C. to
45.degree. C. The mixture was stirred at 35.degree. C. to
45.degree. C. for 2 hours and 3 minutes and then the mixture was
cooled to -5.degree. C. to +5.degree. C. over 2 hours and 3
minutes. The slurry was stirred at -5.degree. C. to +5.degree. C.
for 37 minutes and filtered. The cake was washed with a mixture of
MTBE (43.6 kg) and ethanol (8.2 kg), followed by 100% MTBE (52.3
kg). The wet cake (26.25 kg) was dried at not more than 25.degree.
C. to yield 25.42 kg of
(R)-1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl) cyclohexanol
hydrochloride monohydrate.
[0268] These examples provide various exemplary methods of
synthesis of (-)-O-desmethylvenlafaxine. Alternate methods of
synthesizing (-)-O-desmethylvenlafaxine will be apparent to those
of skill in the art.
6.3 Example 2
Determination of Potency and Specificity
[0269] Several methods useful for the determination of the potency
and specificity of the compounds of this invention are disclosed in
the literature. See, e.g., Haskins, J. T. et al. Euro. J.
Pharmacol. 115:139-146 (1985). In some embodiments, methods that
have been found particularly useful are disclosed by Muth, E. A. et
al. Biochem. Pharmacol. 35:4493-4497 (1986) and Muth, E. A. et al.
Drug Develop. Res. 23:191-199 (1991), both of which are
incorporated herein by reference.
6.3.1 Receptor Binding
[0270] Determination of receptor binding of the compounds of this
invention preferably is performed by the methods disclosed by Muth
et al., and using the protocols summarized in U.S. Pat. Nos.
6,342,533 B1, 6,441,048 B1 and 6,911,479 B2.
[0271] The tissue homogenates used are preferably whole brain
except cerebellum (histamine-1 and opiate binding), cortex
(.alpha..sub.1 adrenergic receptor binding, monoamine uptake); and
striatum (dopamine-2 and muscarinic cholinergic receptor
binding).
6.3.2 Synaptosomal Uptake Studies
[0272] These studies may be performed using the modified
methodology of Wood, M. D., and Wyllie, M. G. J. Neurochem.
37:795-797 (1981) as described in Muth et al. Biochem. Pharmacol.
35:4493-4497 (1986). Briefly, a P2 pellet is prepared from fresh
rat brain tissue by sucrose density gradient centrifugation using a
vertical rotor. For uptake studies, all components are dissolved in
the following buffer: 135 mM NaCl, 5 mM KCl, 1.2 mM MgCl.sub.2, 2.5
mM CaCl.sub.2, 10 mM glucose, 1 mM ascorbic acid, 20 mM Tris, pH
7.4, gassed with O.sub.2 for 30 min prior to use. Various
concentrations of test drug are preincubated with 0.1 .mu.M
[.sup.3H]dopamine or 0.1 .mu.M [.sup.3H]norepinephrine (130,000
dpm/tube) and 0.1 .mu.M [.sup.14C]serotonin (7,500 dpm/tube) in 0.9
ml buffer for 5 min at 37.degree. C. One-tenth milliliter of
synaptosomal preparation is added to each tube and incubated for a
further 4 min at 37.degree. C. The reaction is then terminated by
the addition of 2.5 ml buffer, after which the mixture was filtered
under vacuum using cellulose acetate filters (0.45 .mu.M pore
size). The filters are then counted in a scintillation counter, and
the results are expressed as pmoles uptake/mg protein/min. The IC50
values for uptake inhibition are calculated by linear regression of
log [percent of Na.sup.+-dependent uptake] vs. log [concentration
of test drug].
6.3.3 Reversal of Reserpine-Induced Hypothermia
[0273] Reversal of reserpine-induced hypothermia in male CF-1 mice
(20-25 g., Charles River) may be performed according to an
adaptation of the method of Askew, B. Life Sci. 1:725-730 (1963).
Test compounds, suspended or solubilized in 0.25% Tween80.RTM. in
water, are then administered i.p. at several dose levels to male
mice (8/dose level) who had been treated 18 hr previously with 45.0
mg/kg reserpine s.c. A vehicle control group is run simultaneously
with drug groups. Test compounds, vehicle, and reserpine are
administered at a volume of 0.01 ml/g. Reserpine is solubilized by
the addition of a small amount (approximately 4 drops) of
concentrated acetic acid and then brought to the proper volume by
the addition of distilled water. Rectal temperatures are recorded
by a Yellow Springs Instruments thermistor probe at a depth of 2
cm. Measurements are taken 18 hr after reserpine pretreatment and
at hourly intervals for 3 hr following administration of either
test compound or vehicle.
[0274] Rectal temperatures for all time periods are subjected to a
two-way analysis of variance for repeated measures with subsequent
Dunnett's comparison to control values to determine the minimum
effective dose (MED) for antagonizing reserpine-induced
hypothermia.
6.3.4 Induction of Rat Pineal Noradrenergic Subsensitivity
[0275] Suitable rats are male Sprague-Dawley rats (250-300 g,
Charles River) which should be maintained in continuous light
throughout all experiments so as to attenuate the diurnal
fluctuation in beta-adrenergic receptor density in the pineal gland
and to maintain a consistent supersensitive response to
noradrenergic agonists (Moyer, J. A. et al. Soc. Neurosci. Abstract
10:261 (1984)). After 2 days of continuous light exposure, the rats
are then injected twice daily with either saline or test compound
(10 mg/kg i.p.) for 5 days (total of 9 injections). Another group
of rats should receive saline injections twice daily for 4 days
followed by a single injection of test compound (10 mg/kg i.p.) on
the 5th day. One hour following the final injection of test
compound or saline, animals are administered either 0.1% ascorbic
acid (controls), or isoproterenol (2 .mu.mol/kg i.p. in 0.1%
ascorbic acid). Rats are decapitated 2.5 minutes later, the time at
which preliminary experiments have shown that the
isoproterenol-induced increases in cyclic AMP levels in pineal
glands are maximal (Moyer, J. A. et al. Mol. Pharmacol. 19:187-193
(1981)). Pineal glands are removed and frozen on dry ice within 30
seconds to minimize any post-decapitation increase in cAMP
concentration.
[0276] Prior to radioimmunoassay for cAMP, the pineal glands are
placed in 1 ml of ice-cold 2.5% perchloric acid and sonicated for
approximately 15 seconds. The sonicate is then centrifuged at
49.000 g for 15 min at 4.degree. C. and then resulting supernatant
fluid is removed, neutralized with excess CaCO.sub.3, and
centrifuged at 12,000 g for 10 min at 4.degree. C. The cAMP content
of the neutralized extract may be measured by a standard
radioimmunoassay using 125I-labeled antigen and antiserum (New
England Nuclear Corp., Boston, Mass.; Steiner, A. L. et al. J.
Biol. Chem. 247:1106-1113 (1972)). All unknown samples should be
assayed in duplicate and compared to standard solutions of cAMP
prepared in a 2.5% perchloric acid solution that had been
neutralized with CaCO.sub.3. Results are expressed as pmol
cAMP/pineal, and statistical analyses are performed by analysis of
variance with subsequent Student-Newman-Keuls tests.
6.3.5 Single Unit Electrophysiology
[0277] The firing rates of individual neurons of the locus
coeruleus (LC) or dorsal raphe nucleus (DR) in the chloral-hydrate
anesthetized rat are measured using single-barreled glass
micro-electrodes as previously described in LC. Haskins, J. T. et
al. Eur. J. Pharmacol. 115:139-146 (1985). Using the stereotaxic
orientation of Konig, J. F. R., and Klippel, R. A. The rat brain: A
stereotaxic atlas of the forebrain and lower parts of the brain
stem Baltimore: Williams and Wilkins (1963), the electrode tips
should be lowered via a hydraulic microdrive from a point 1.00 mm
above the locus coeruleus (AP 2.00 mm caudal to the interaural line
and 1.03 mm lateral to midline). Drugs are administered i.v.
through a lateral tail vein cannula. Only one cell should be
studied in each rat in order to avoid residual drug effects.
6.4 Example 3
Oral Formulation
[0278] The pharmaceutical compositions of this invention may be
administered in a variety of ways, including orally.
6.4.1 Hard Gelatin Capsule Dosage Forms
[0279] The ingredients of suitable capsule forms of the
pharmaceutical compositions of this invention may be found in U.S.
Pat. Nos. 6,342,533 B1, 6,441,048 B1 and 6,911,479 B2.
[0280] The active ingredient (optically pure
(-)-O-desmethylvenlafaxine, or pharmaceutically acceptable salt
thereof) is sieved and blended with the excipients listed. The
mixture is filled into suitably sized two-piece hard gelatin
capsules using suitable machinery and methods well known in the
art. See Remington's Pharmaceutical Sciences, 16th or 18th
Editions, each incorporated herein in its entirety by reference
thereto. Other doses may be prepared by altering the fill weight
and, if necessary, by changing the capsule size to suit. Any of the
stable hard gelatin capsule formulations above may be formed.
6.4.2 Compressed Tablet Dosage Forms
[0281] The ingredients of compressed tablet forms of the
pharmaceutical compositions of the invention may be found in U.S.
Pat. Nos. 6,342,533 B1, 6,441,048 B1 and 6,911,479 B2.
[0282] The active ingredient is sieved through a suitable sieve and
blended with the excipients until a uniform blend is formed. The
dry blend is screened and blended with the magnesium stearate. The
resulting powder blend is then compressed into tablets of desired
shape and size. Tablets of other strengths may be prepared by
altering the ratio of the active ingredient to the excipient(s) or
modifying the tablet weight.
6.4.3 Example of a Capsule Formulation
TABLE-US-00001 [0283] 50 mg 100 mg (mg/capsule) (mg/capsule) (-)-O-
60.34 120.68 desmethylvenlafaxine hydrochloride monohydrate
Microcrystalline 60.00 19.02 cellulose (Avicel PH102) Lactose,
Anhydrous 160.16 103.40 Sodium Starch 18.00 15.60 Glycolate
(Primojel) Magnesium Stearate 1.50 1.30 Total Mass 300.0 260.0
6.4.4 A Delayed Release Formulation
[0284] Several Delayed release formulations have been examined. It
was found the addition of more Methocel K4M CR decreased the
dissolution rate. Tablets have been manufactured using the
formulations outlined below.
Premix Granulation
TABLE-US-00002 [0285] Ingredients Premix Formula SEP-227162-01 605
Avicel pH 102 60.5 Surelease (15% w/w) 21.42
Final Formulations
TABLE-US-00003 [0286] Formulation Formulation B Ingredients A (mg)
(mg) Formulation C (mg) Premix 687.00 687.00 687.00 Methocel K4M CR
30.25 60.5 121.00 Mag. Stearate 7.00 7.00 8.00 Tablet weight 724.25
754.50 816.00
6.5 Example 4
Crystallization and Characterization of Form A of the Hydrochloride
Salt of (-)-O-Desmethylvenlafaxine
6.5.1 Crystallization
[0287] (-)-O-desmethylvenlafaxine was crystallized as Form A of the
HCl salt of (-)-O-desmethylvenlafaxine. The freebase of
(-)-O-desmethylvenlafaxine was prepared according to Example 1.
Form A of the HCl salt of (-)-O-desmethylvenlafaxine was prepared
from Form B of (-)-O-desmethylvenlafaxine HCl salt, described
below, according to the following procedure: A 3.09 gram sample of
(-)-O-desmethylvenlafaxine hydrochloride salt (form B) was placed
in a 70.times.50 mm crystallization dish and stored at 40.degree.
C./75% RH for 3 days. The sample was then dried under vacuum at
ambient temperature for 2 days.
[0288] The Form A crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine prepared according to the procedure
above was characterized by analytical techniques including thermal
gravimetric analysis, differential scanning calorimetry, X-ray
powder diffraction, moisture sorption, infrared spectroscopy and
Raman spectroscopy, according to the analytical parameters
described supra.
6.5.1.1 Single Crystal X-Ray Diffraction Data of Form A
[0289] Crystals of Form A of the HCl salt of
(-)-O-desmethylvenlafaxine suitable for single crystal X-ray
diffraction were prepared by solvent/antisolvent techniques from a
water/2-methyl-tetrahydrofuran solvent system. Single-crystal X-ray
diffraction analysis was performed using a Nonius K.alpha. ppa CCD
diffractometer with Mo K.alpha. radiation (.lamda.=0.71073 .ANG.).
Refined mosaicity was obtained using DENZO/SCALEPACK (Otwinowski
and Minor, Methods Enzymol. 276:307 (1997)). The space group was
determined using the program XPREP (Bruker AXS Inc., Madison, Wis.,
USA, (2002)). Data integration was performed with DENZO-SMN
(Otwinowski and Minor, Methods Enzymol. 276:307 (1997)). An
empirical absorption correction was applied, obtained using
SCALEPACK (Otwinowski and Minor, Methods Enzymol. 276: 307 (1997)).
The structure was solved by direct methods using SIR2004 (Burla et
al., J. Appl. Cryst., 36:1103 (2003)), and refinements were
performed on an LINUX PC using SHELX97 (Sheldrick, University of
Gottingen, Germany, (1997)). The absolute configuration of the
(-)-O-desmethylvenlafaxine molecule was deduced using information
from the structure solution of another crystal form (Form F,
described below) obtained using the same (-)-O-desmethylvenlafaxine
starting material. Data collection and structure parameter details
are shown in Table I.
[0290] An ORTEP drawing of the asymmetric unit from the single
crystal structure solution of the Form A crystal form of the HCl
salt of (-)-O-desmethylvenlafaxine is shown in FIG. 7 (ORTEP-3 for
Windows, v. 1.05. Farrugia, J. Appl. Cryst., 30:565 (1997)). The
asymmetric unit shown in the drawing contains one
(-)-O-desmethylvenlafaxine cation, one chloride anion and one water
molecule.
TABLE-US-00004 TABLE I Crystal Data and Data Collection Parameters
for Form A of the HCl salt of (-)-O-desmethylvenlafaxine. formula
C.sub.16H.sub.28ClNO.sub.3 formula weight 317.85 space group
P2.sub.12.sub.12.sub.1 (No. 19) Unit cell dimensions a = 6.7797(2)
.ANG.; .alpha. = 90.degree.. b = 9.2896(4) .ANG.; .beta. =
90.degree.. c = 27.6496(15) .ANG.; .gamma. = 90.degree.. Volume
1741.39(13) .ANG..sup.3 Z 4 d.sub.calc, g cm.sup.-3 1.212 crystal
dimensions, mm 0.46 .times. 0.13 .times. 0.04 temperature, K 150
radiation (wavelength, .ANG.) Mo K.sub.a (0.71073) monochromator
graphite linear abs coef, mm.sup.-1 0.226 absorption correction
applied empirical.sup.a transmission factors: min, max 0.916, 0.992
diffractometer Nonius Kappa CCD h, k, l range -8 to 7 -11 to 11 -33
to 34 2.theta. range, deg 4.38-52.21 mosaicity, deg 0.38 programs
used SHELXTL F.sub.000 688.0 weighting
1/[.sigma..sup.2(F.sub.o.sup.2) + (0.0000P).sup.2 + 1.9052P] 11326
where P = ( F.sub.o.sup.2 + 2F.sub.c.sup.2)/3 data collected unique
data 2273 R.sub.int 0.155 data used in refinement 2273 cutoff used
in R-factor calculations F.sub.o.sup.2 > 2.0sigma(F.sub.o.sup.2)
data with I > 2.0sigma(I) 2018 number of variables 208 largest
shift/esd in final cycle 0.00 R (F.sub.o) 0.071 R.sub.w
(F.sub.o.sup.2) 0.105 goodness of fit 1.225 absolute structure
determination Flack parameter (0.1(2))
[0291] A simulated X-ray powder diffraction pattern was generated
for Cu radiation using PowderCell 2.3 (Kraus and Nolze, Federal
Institute for Materials Research and Testing, Berlin, Germany,
(1999)) with the atomic coordinates, space group, and unit cell
parameters from the single crystal data of Form A; see FIG. 8. The
Form A experimental X-ray powder diffraction pattern matched the
pattern simulated from the single crystal X-ray diffraction data.
Slight shifts in XRPD peak location resulted from small changes in
the unit cell parameters due to temperature differences: the
calculated X-ray powder diffraction pattern was generated from the
single crystal data which was collected at 150 K, while the
experimental powder pattern was collected at ambient temperature.
Collecting data at low temperature is typically used in single
crystal analysis to improve the quality of the data.
6.6 Example 5
Crystallization and Characterization of Form B of the Hydrochloride
Salt of (-)-O-Desmethylvenlafaxine
6.6.1 Crystallization
[0292] (-)-O-desmethylvenlafaxine was crystallized as Form B of the
HCl salt of (-)-O-desmethylvenlafaxine. (-)-O-Desmethylvenlafaxine
was prepared according to Example 1. 5.07 g of the HCl salt of
(-)-O-desmethylvenlafaxine was dissolved in 400 mL of
tetrahydrofuran at 40 .degree. C. The solution was cooled to
25.degree. C. and 10.6 mL of 2.0 M HCl in diethyl ether was added.
The mixture was cooled to 0.degree. C. and filtered. The cake was
washed with 20 mL of THF and dried in vacuo at ambient temperature
to yield 6.09 g of Form B of
1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl) cyclohexanol
hydrochloride.
6.6.2 Characterization
[0293] The Form B crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine prepared according to the procedure
above was characterized by techniques such as X-ray powder
diffraction, differential scanning calorimetry, thermal gravimetric
analysis, moisture sorption, infrared spectroscopy and Raman
spectroscopy, according to the analytical parameters described
above.
6.7 Example 6
Crystallization and Characterization of Form C of the Hydrochloride
Salt of (-)-O-Desmethylvenlafaxine
6.7.1 Crystallization
[0294] (-)-O-Desmethylvenlafaxine was crystallized as Form C of the
HCl salt of (-)-O-desmethylvenlafaxine. (-)-O-Desmethylvenlafaxine
was prepared according to Example 1. 0.18 g of
(-)-O-desmethylvenlafaxine and 0.35 mL of 37 wt % aqueous
hydrochloric acid were mixed at 60.degree. C. for 1 h. The mixture
was cooled to 0.degree. C., filtered and washed with ethyl acetate.
The solid was dried in vacuo at ambient temperature to yield 0.22 g
of 1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl) cyclohexanol
hydrochloride.
6.7.2 Characterization
[0295] The Form C crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine prepared according to the procedure
above was characterized by techniques such as X-ray powder
diffraction, differential scanning calorimetry, thermal gravimetric
analysis, moisture sorption, infrared spectroscopy and Raman
spectroscopy, according to the analytical parameters described
above.
6.8 Example 7
Crystallization and Characterization of Form D of the Hycrochloride
Salt of (-)-O-Desmethylvenlafaxine 6.8.1 Crystallization
[0296] (-)-O-desmethylvenlafaxine was crystallized as Form D of the
HCl salt of (-)-O-desmethylvenlafaxine. (-)-O-desmethylvenlafaxine
was prepared according to Example 1. Form A (42.8 mg) of
(-)-O-desmethylvenlafaxine HCl salt, obtained as described in
Example 4, was weighed into a vial, and 0.5 mL of IPA was added.
The sample was sonicated, and became very thick. The solids were
isolated by vacuum filtration, and the sample was air dried in a
hood. After a day of drying, the sample was stored at ambient
conditions for four days, at which point the XRPD analysis was
performed.
6.8.2 Characterization
[0297] The Form D crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine prepared according to the procedure
above was characterized by techniques such as X-ray powder
diffraction, differential scanning calorimetry and thermal
gravimetric analysis, according to the analytical parameters
described above.
6.9 Example 8
Chrystallizatoin and Characterization of Form E of the
Hycrochloride Salt of (-)-O-Desmethylvenlafaxine
6.9.1 Crystallization
[0298] (-)-O-Desmethylvenlafaxine was crystallized as Form E of the
HCl salt of (-)-O-desmethylvenlafaxine. (-)-O-Desmethylvenlafaxine
was prepared according to Example 1. 0.35 mL of 37 wt % aqueous
hydrochloric acid was added to 5.0 g of (-)-O-desmethylvenlafaxine
in 25 mL of methanol. The resulting solution was stirred at
25.degree. C. for 20 minutes. The methanol/hydrochloric acid
solution was added with stirring to 300 mL of methyl-tert butyl
ether at 25.degree. C. Following the addition of the
methanol/hydrochloric acid solution the mixture was stirred at
25.degree. C. for 2 hours and then the solid was collected by
filtration and washed with 20 mL of MTBE. The solid was air dried
at ambient temperature to yield 5.4 g of Form E of
1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol
hydrochloride.
6.9.2 Characterization
[0299] The Form E crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine prepared according to the procedure
above was characterized by techniques such as X-ray powder
diffraction, differential scanning calorimetry, thermal gravimetric
analysis, moisture sorption, infrared spectroscopy and Raman
spectroscopy, according to the analytical parameters described
above.
6.10 Example 9
Chrystallizatoin and Characterization of Form F of the HCl Salt of
(-)-O-Desmethylvenlafaxine
6.10.1 Crystallization
[0300] Form A of the HCl salt of (-)-O-desmethylvenlafaxine (19.47
mg) was weighed into a vial, and 3 mL of ethyl acetate was added.
Solids remained after sonication. The sample was placed on a hot
plate set at 75.degree. C., and stirred using a magnetic stirrer
set at 350 rpm. After approximately 2.5 hours of stirring at
75.degree. C., the sample was syringe filtered into a warm, 1-dram
vial. (Prior to filtering, the filter, syringe, and vial were
warmed on the hot plate with the sample.) The sample was capped,
set on the bench top, and allowed to cool to ambient temperature.
The sample was vacuum filtered and analyzed as Form F.
6.10.2 Characterization
[0301] The Form F crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine prepared according to the procedure
above was characterized by techniques such as X-ray powder
diffraction, differential scanning calorimetry, thermal gravimetric
analysis, moisture sorption, infrared spectroscopy and Raman
spectroscopy, according to the analytical parameters described
above.
6.10.2.1 Single Crystal X-Ray Diffraction Data of Form F
[0302] Crystals of Form F of the HCl salt of
(-)-O-desmethylvenlafaxine suitable for single crystal X-ray
diffraction were prepared by a vapor diffusion technique. Three
milliliters of 2-butanone were added to 7.71 mg of Form A, obtained
as described above. Not all of the solids dissolved. The sample was
filtered into a 1 dram vial. The vial was placed into a 20 mL
scintillation vial containing toluene. The larger vial was then
capped, and the sample was allowed to equilibrate. Single crystals
of Form F were isolated, and the structure was solved.
[0303] Single-crystal X-ray diffraction analysis was performed
using a Bruker D8 APEX II CCD sealed tube diffractometer with Cu
K.alpha. radiation (.lamda.=1.54178 .ANG.). Data collection,
indexing and initial cell refinements were all carried out using
the software APEX II (Bruker AXS, Inc., Madison, Wis., USA,
(2005)). Frame integration and final cell refinements were done
using the software SAINT (v. 6.45A, Bruker AXS, Inc., Madison,
Wis., USA (2003)). The space group was determined by the program
XPREP (SHELXTL v. 6.12, Bruker AXS, Inc., Madison, Wis., USA). An
empirical absorption correction was applied using SADABS (Blessing,
Acta Cryst., A51:33 (1995)). The structure was solved by direct
methods using SHELXS-97 (Sheldrick, University of Gottingen,
Germany, (1997)). Refinements were performed on a PC using SHELXTL
(v. 6.12, Bruker AXS, Inc., Madison, Wis., USA). The absolute
configuration of the (-)-O-desmethylvenlafaxine molecule was
deduced by assessing the Flack factor (Flack and Bernardinelli,
Acta Cryst, A55: 908 (1999), and J. Appl. Cryst., 33:1143 (2000)).
Data collection and structure parameter details are shown in Table
2.
[0304] An ORTEP drawing of the asymmetric unit from the single
crystal structure solution of the Form F crystal form of the HCl
salt of (-)-O-desmethylvenlafaxine is shown in FIG. 37 (ORTEP-3 for
Windows, v. 1.05. Farrugia, J. Appl. Cryst, 30:565 (1997)). The
asymmetric unit shown in the drawing contains one
(-)-O-desmethylvenlafaxine cation, one chloride anion and one water
of hydration.
TABLE-US-00005 TABLE 2 Crystal Data and Data Collection Parameters
for Form F of the HCl salt of (-)-O-desmethylvenlafaxine. Empirical
formula C.sub.16H.sub.28ClNO.sub.3 formula weight 317.85
Temperature 173(2) K Wavelength 1.54178 .ANG. Crystal system
Monoclinic Space group P2(1) Unit cell dimensions a = 9.2881(2)
.ANG.; .alpha. = 90.degree.. b = 6.8185(2) .ANG.; .beta. =
92.580(1).degree.. c = 13.9085(3) .ANG.; .gamma. = 90.degree..
Volume 879.95(4) .ANG..sup.3 Z 2 Density (calculated) 1.200
Mg/m.sup.3 Absorption coefficient 1.996 mm.sup.-1 F(000) 344
Crystal size 0.43 .times. 0.25 .times. 0.18 mm.sup.3 Theta range
for data collection 8.07 to 65.77.degree.. Index ranges -10 <= h
<= 10, -6 <= k <= 6, -16 <= l <= 15 Reflections
collected 3464 Independent reflections 1722 [R(int) = 0.0131]
Completeness to theta = 65.77.degree. 76.1% Absorption correction
Semi-empirical from equivalents Max. and min. transmission 0.7152
and 0.4807 Refinement method Full-matrix least-squares on F.sup.2
Data/restraints/parameters 1722/1/194 Goodness-of-fit on F.sup.2
1.034 Final R indices [I > 2sigma(I)] R1 = 0.0265, wR2 = 0.0714
R indices (all data) R1 = 0.0268, wR2 = 0.0716 Absolute structure
parameter 0.034(13) Largest diff. peak and hole 0.129 and -0.185 e
.ANG..sup.-3
[0305] A simulated X-ray powder diffraction pattern was generated
for Cu radiation using PowderCell 2.3 (Kraus and Nolze, Federal
Institute for Materials Research and Testing, Berlin, Germany,
(1999)) and the atomic coordinates, space group, and unit cell
parameters from the single crystal data of Form F; see FIG. 33. The
Form F experimental X-ray powder diffraction pattern matched the
pattern simulated from the single crystal X-ray diffraction data.
Differences in intensities may have resulted from preferred
orientation. Preferred orientation is the tendency for crystals,
usually plates or needles, to align in a non-random manner.
Preferred orientation affects peak intensities in X-ray powder
diffraction patterns. Slight shifts in peak location may have
resulted from experimental temperature differences: the
experimental powder pattern was collected at ambient temperature,
while the single crystal data was collected at 173 K. Certain Form
F samples which were isolated as physical mixtures with Form A
exhibited peaks characteristic of Form A in the XRPD pattern, which
were not present in the simulated Form F XRPD pattern.
6.11 Example 10
Chrystallizatoin and Characterization of Form G of the
Hycrochloride Salt of (-)-O-Desmethylvenlafaxine
6.11.1 Crystallization
[0306] (-)-O-desmethylvenlafaxine was crystallized as Form G of the
HCl salt of (-)-O-desmethylvenlafaxine. (-)-O-desmethylvenlafaxine
was prepared according to Example 1. The Form A crystal form of
(-)-O-desmethylvenlafaxine (31.50 mg), prepared according to
Example 4, was placed into a 20 mL scintillation vial, which was
placed, uncapped, into a P.sub.2O.sub.5 chamber at ambient
temperature. After three days, the chamber containing the sample
was placed into a 70.degree. C. oven. Analysis performed ten days
after the sample was placed in the oven indicated that the sample
was Form G.
6.11.2 Characterization
[0307] The Form G crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine prepared according to the procedure
above was characterized by techniques such as X-ray powder
diffraction, differential scanning calorimetry, thermal gravimetric
analysis and moisture sorption, according to the analytical
parameters described above.
6.12 Example 11
Chrystallizatoin and Characterization of Form H of the
Hycrochloride Salt of (-)-O-Desmethylvenlafaxine
6.12.1 Crystallization
[0308] (-)-O-desmethylvenlafaxine was crystallized as Form H of the
HCl salt of (-)-O-desmethylvenlafaxine. (-)-O-desmethylvenlafaxine
was prepared according to Example 1. Form H was prepared by
slurring Form A of the HCl salt of (-)-O-desmethylvenlafaxine in
acetone on a hot plate set at 55.degree. C. The samples were
stirred in half dram vials on the hot plate using a magnetic
stirrer set at 300 rpm. In each case, 0.5 mL of acetone was used.
One sample contained 42.13 mg of the HCl salt of
(-)-O-desmethylvenlafaxine, and was slurried for three days prior
to isolation of Form H. A second sample was filtered after one day,
and contained 48.13 mg of the HCl salt of
(-)-O-desmethylvenlafaxine. A third sample, slurried for an
unspecified time, contained 41.91 mg of the HCl salt of
(-)-O-desmethylvenlafaxine. The solids thus obtained were
characterized as the Form H crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine.
6.12.2 Characterization
[0309] The Form H crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine prepared according to the procedure
above was characterized by techniques such as X-ray powder
diffraction, differential scanning calorimetry and thermal
gravimetric analysis, according to the analytical parameters
described above.
6.13 Example 12
Chrystallizatoin and Characterization of Form I of the
Hycrochloride Salt of (-)-O-Desmethylvenlafaxine
6.13.1 Crystallization
[0310] (-)-O-desmethylvenlafaxine was crystallized as Form I of the
HCl salt of (-)-O-desmethylvenlafaxine. (-)-O-desmethylvenlafaxine
was prepared according to Example 1. Form I was precipitated from
isopropanol. One sample was prepared by dissolving 46.01 mg of Form
A of the HCl salt of (-)-O-desmethylvenlafaxine in 0.5 mL
isopropanol using sonication. The sample was prepared in a 1-dram
vial. Precipitation was observed after approximately 10-15 minutes.
The solids were isolated by vacuum filtration. The second sample
was prepared using the procedure described for the first sample,
except that 25.86 mg of Form A of the HCl salt of
(-)-O-desmethylvenlafaxine was dissolved. Precipitation for this
second sample was observed after approximately ten minutes.
Following synthesis, solids were isolated and characterized as the
Form I crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine.
6.13.2 Characterization
[0311] The Form I crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine prepared according to the procedure
above was characterized by techniques such as X-ray powder
diffraction, differential scanning calorimetry and thermal
gravimetric analysis, according to the analytical parameters
described above.
6.14 Example 13
Chrystallizatoin and Characterization of Form J of the
Hycrochloride Salt of (-)-O-Desmethylvenlafaxine
6.14.1 Crystallization
[0312] (-)-O-desmethylvenlafaxine was crystallized as Form J of the
HCl salt of (-)-O-desmethylvenlafaxine. (-)-O-desmethylvenlafaxine
was prepared according to Example 1. Form J of the HCl salt of
(-)-O-desmethylvenlafaxine was prepared by slurring Form A in
acetonitrile for approximately one day on a hot plate set at
55.degree. C. Form A of the HCl salt of (-)-O-desmethylvenlafaxine
(43.66 mg) was weighed into a 1-dram vial, and 0.5 mL of
acetonitrile was added. Solids remained after sonication. The
sample was stirred on the hot plate using a magnetic stirrer set at
300 rpm. After a day, the solvent was decanted. The solids thus
obtained were characterized as the Form J crystal form of the HCl
salt of (-)-O-desmethylvenlafaxine.
6.14.2 Characterization
[0313] The Form J crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine prepared according to the procedure
above was characterized by techniques such as X-ray powder
diffraction, and NMR spectroscopy, according to the analytical
parameters described above. About 0.2 mole of acetonitrile per mole
of the HCl salt of (-)-O-desmethylvenlafaxine was present in a Form
J sample, as observed using NMR spectroscopy.
6.15 Example 14
Chrystallizatoin and Characterization of Form K of the
Hycrochloride Salt of (-)-O-Desmethylvenlafaxine
6.15.1 Crystallization
[0314] (-)-O-desmethylvenlafaxine was crystallized as Form K of the
HCl salt of (-)-O-desmethylvenlafaxine. (-)-O-desmethylvenlafaxine
was prepared according to Example 1. Form K of the HCl salt of
(-)-O-desmethylvenlafaxine was prepared from a vapor diffusion
experiment using ethanol as the solvent and acetone as the
antisolvent. The sample was prepared by adding 0.3 mL of ethanol to
22.20 mg of Form A of the HCl salt of (-)-O-desmethylvenlafaxine.
The sample dissolved and was filtered into a 1-dram vial. The vial
was placed into a 20 mL scintillation vial containing acetone. The
larger vial was then capped, and the sample was allowed to
equilibrate. Single crystals were isolated from this experiment.
The crystals thus obtained were characterized as the Form K crystal
form of the HCl salt of (-)-O-desmethylvenlafaxine.
6.15.2 Characterization
[0315] The Form K crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine prepared according to the procedure
above was characterized by techniques such as X-ray powder
diffraction, and single-crystal X-ray diffraction, according to the
analytical parameters described above.
6.15.2.1 Single crystal X-ray diffraction data of Form K
[0316] Crystals of Form K of the HCl salt of
(-)-O-desmethylvenlafaxine suitable for single crystal X-ray
diffraction were prepared by the technique described above.
Single-crystal X-ray diffraction analysis was performed using a
Bruker D8 APEX II CCD sealed tube diffractometer with Cu K.alpha.
radiation (A =1.54178 .ANG.). Data collection, indexing and initial
cell refinements were all carried out using the software APEX II
(Bruker AXS, Inc., Madison, Wis., USA (2005)). Frame integration
and final cell refinements were done using the software SAINT (v.
6.45A, Bruker AXS, Inc., Madison, Wis., USA (2003)). The space
group was determined by the program XPREP (SHELXTL v. 6.12, Bruker
AXS, Inc., Madison, Wis., USA). An empirical absorption correction
was applied using SADABS (Blessing, Acta Cryst, A51:33 (1995)). The
structure was solved by direct methods using SHELXS-97 (Sheldrick,
University of Gottingen, Germany, (1997)). Refinements were
performed on a PC using SHELXTL (v. 6.12, Bruker AXS, Inc.,
Madison, Wis., USA). The absolute configuration of the
(-)-O-desmethylvenlafaxine molecule was deduced by assessing the
Flack factor (Flack and Bernardinelli, Acta Cryst, A55:908 (1999),
and J. Appl. Cryst., 33:1143 (2000)). Data collection and structure
parameter details are shown in Table 3.
[0317] The complete contents of the asymmetric unit of the crystal
structure of Form K includes two (-)-O-desmethylvenlafaxine
cations, two chloride anions and one partially occupied, highly
disordered ethanol molecule. Since the ethanol molecule is not
fully occupied, Form K is termed a partial ethanol solvate.
TABLE-US-00006 TABLE 3 Crystal Data and Data Collection Parameters
for Form K of the HCl salt of (-)-O-desmethylvenlafaxine. Empirical
formula C.sub.16H.sub.26ClNO.sub.2.cndot.0.14(C.sub.2H.sub.6O)
Formula weight 306.33 Temperature 173(2) K Wavelength 1.54178 .ANG.
Crystal system Monoclinic Space group C2 Unit cell dimensions a =
30.056(3) .ANG.; .alpha. = 90.degree.. b = 7.7375(8) .ANG.; .beta.
= 134.502(4).degree.. c = 21.208(4) .ANG.; .gamma. = 90.degree..
Volume 3517.7(8) .ANG..sup.3 Z 8 Density (calculated) 1.157
Mg/m.sup.3 Absorption coefficient 1.944 mm.sup.-1 F(000) 1322
Crystal size 0.53 .times. 0.08 .times. 0.06 mm.sup.3 Theta range
for data collection 7.37 to 44.67.degree.. Index ranges -27 <= h
<= 25, -7 <= k <= 7, -19 <= l <= 19 Reflections
collected 2985 Independent reflections 2063 [R(int) = 0.0413]
Completeness to theta = 44.67.degree.. Absorption correction
Semi-empirical from equivalents Max. and min. transmission 0.8923
and 0.4256 Refinement method Full-matrix least-squares on F.sup.2
Data/restraints/parameters 2063/2/378 Goodness-of-fit on F.sup.2
1.060 Final R indices [I > 2sigma(I)] R1 = 0.0518, wR2 = 0.1391
R indices (all data) R1 = 0.0800, wR2 = 0.1571 Absolute structure
parameter 0.01(4) Largest diff, peak and hole 0.464 and -0.545 e
.ANG..sup.-3
[0318] A simulated X-ray powder diffraction pattern was generated
for Cu radiation using PowderCell 2.3 (Kraus and Nolze, Federal
Institute for Materials Research and Testing, Berlin, Germany
(1999)) and the atomic coordinates, space group, and unit cell
parameters from the single crystal data of Form K; see FIG. 50. The
Form K experimental X-ray powder diffraction pattern matched the
pattern simulated from the single crystal X-ray diffraction data.
Differences in intensities may have resulted from preferred
orientation. Slight shifts in peak location may have resulted from
experimental temperature differences: the experimental powder
pattern was collected at ambient temperature, while the single
crystal data was collected at 173 K.
6.16 Example 15
Chrystallizatoin and Characterization of Form L of the
Hycrochloride Salt of (-)-O-Desmethylvenlafaxine
6.16.1 Crystallization
[0319] (-)-O-desmethylvenlafaxine was crystallized as Form L of the
HCl salt of (-)-O-desmethylvenlafaxine. (-)-O-desmethylvenlafaxine
was prepared according to Example 1. Form L was prepared from a
prolonged ambient temperature slurry in 2-methyl-tetrahydrofuran.
The sample was prepared by adding 20 mL of 2-methyl-tetrahydrofuran
to 38.75 mg of Form A of the HCl salt of
(-)-O-desmethylvenlafaxine. A 20 mL scintillation vial was used for
the experiment, and the 2-methyl-tetrahydrofuran was added slowly.
Solids were present after the solvent addition, and the sample was
capped and placed on a rotating wheel at ambient temperature. After
97 days on the wheel, the sample of Form L was removed, vacuum
filtered, and submitted for analysis. The solids thus obtained were
characterized as the Form L crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine.
6.16.2 Characterization
[0320] The Form L crystal form of the HCl salt of
(-)-O-desmethylvenlafaxine prepared according to the procedure
above was characterized by techniques such as X-ray powder
diffraction, differential scanning calorimetry, thermal gravimetric
analysis and NMR spectroscopy, according to the analytical
parameters described above. Between about 0.13 and 0.14 mole of
2-methyl-tetrahydrofuran per mole of the HCl salt of
(-)-O-desmethylvenlafaxine was present in a Form L sample, as
observed using NMR spectroscopy.
6.17 Example 16
Preparation and Characterization of A Desolvated Solvate Form of a
Hydrochloride Salt of (-)-O-Desmethylvenlafaxine
6.17.1 Preparation
[0321] Form C of the HCl salt of (-)-O-desmethylvenlafaxine was
prepared as described above. Form C was heated to 100.degree. C. in
a TGA furnace, according to the procedure described above, and a
weight loss of 5.4% was observed. The material was removed from the
furnace; analysis confirmed that the material was a desolvated
solvate.
6.17.2 Characterization
[0322] The desolvated solvate was analyzed by X-ray powder
diffraction. The locations of the peaks in the X-ray powder
diffraction pattern of the desolvated solvate were similar to the
locations of the XRPD peaks in the Form C starting material. This
data, in conjunction with the TGA weight loss data, indicated that
the solvent evacuated the crystal lattice of Form C while
maintaining structural features of Form C in the form of a
desolvated solvate.
6.18 Example 17
Preparation and Characterization of an Amorphous Form of a
Hydrochloride Salt of (-)-O-Desmethylvenlafaxine
6.18.1 Preparation
[0323] (-)-O-desmethylvenlafaxine was prepared as an amorphous form
of the HCl salt of (-)-O-desmethylvenlafaxine. An aqueous solution
of the HCl salt of (-)-O-desmethylvenlafaxine was prepared,
filtered and frozen. The sample was then placed under vacuum on a
freeze dryer and lyophilized until all solvent had been
removed.
6.18.2 Characterization
[0324] The resulting product was characterized by X-ray powder
diffraction and modulated differential scanning calorimetry. XRPD
data confirmed that the material was amorphous. Based on modulated
differential scanning calorimetry data, the glass transition
temperature of the amorphous form of the HCl salt of
(-)-O-desmethylvenlafaxine was approximately 24.degree. C.
6.19 Example 18
Composition of a Delayed-Release Formulation Comprising a
Hydrochloride Salt of (-)-O-Desmethylvenlafaxine
[0325] (-)-O-Desmethylvenlafaxine HCl and Avicel were mixed inside
the vertical granulator. Pharmacoat 606 was slowly added to the
blend. The wet mass was then tray dried at 45.degree. C. for 2
hours and the semidried blend was then passed through a Fitzmill
using screen size 0109 @ 2000 rpm. The particles were again put
back to the dryer. The dried granules were screened through mesh
#14 and retain on screen #14 was passed through Fitzmill. The
milled particles were mixed with finer screened particles. The
Premix Formulation is summarized in Table 4. Using this Premix, the
Final Formulation was developed, summarized in Table 5.
TABLE-US-00007 TABLE 4 Formulation of Premix Ingredient Quantity
(mg) API: (-)-O-Desmethylvenlafaxine HCl Form A 605 Avicel 105 60.5
Pharmacoat 606 (8% Solution) 11.5
TABLE-US-00008 TABLE 5 Final Formulation Ingredient Formula Premix
677 mg Magnesium Stearate 8 mg Methocel K4M CR 60.5 mg
[0326] In another embodiment, API and Avicel were added to a high
shear granulator and blended briefly. Surelease suspension was
added drop-wise with the high shear process operating. The wet
granulation was removed from the high shear granulator, dried in a
fluid bed dryer, blended with Methocel and magnesium stearate, and
compressed on a suitable tablet machine.
TABLE-US-00009 TABLE 6 Formulation of Premix Ingredient Quantity
(mg) API: (-)-O-Desmethylvenlafaxine HCl form A 484 Avicel pH 102
320 Surelase Suspension 20% w/w (dry wt/susp wt) 80/400 Total
884
TABLE-US-00010 TABLE 7 Matrix Tablets Ingredient Quantity (mg) 50
mg tablet Premix 110.5 Magnesium Stearate 1.5 Methocel K15M CR
213.0 Total 325.0 100 mg tablet Premix 221.0 Magnesium Stearate 3.0
Methocel K 15M CR 276.0 Total 500.0 150 mg tablet Premix 331.5
Magnesium Stearate 4.5 Methocel K15M CR 164.0 Total 500.0
[0327] All publications and patent applications cited in this
specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference. Although
the foregoing invention has been described in some detail by way of
illustration and example for purposes of clarity of understanding,
it will be readily apparent to those of ordinary skill in the art
in light of the teachings of this invention that certain changes
and modifications may be made thereto without departing from the
spirit or scope of the appended claims.
* * * * *